Bipolar Disorder and Glutamate -- Neurotransmitter.net

(Updated 8/25/04)

Michael N, Erfurth A, Ohrmann P, Gossling M, Arolt V, Heindel W, Pfleiderer B.
Acute mania is accompanied by elevated glutamate/glutamine levels within the left dorsolateral prefrontal cortex.
Psychopharmacology (Berl). 2003 Apr 9 [Epub ahead of print].
"RATIONALE. The dorsolateral prefrontal cortex (DLPFC) participates in the pathophysiology of mania. In particular, left-sided structural and metabolic abnormalities have been described. OBJECTIVES. Clinical symptoms may be due to hyperactivity of cortical glutamatergic neurons, resulting in increased excitatory neurotransmitter flux and thus enhanced Glx levels. METHODS. Glutamate/glutamine (Glx) levels were assessed by proton magnetic resonance spectroscopy ((1)H-MRS) in eight acute manic patients compared with age- and gender-matched controls. RESULTS. Manic patients had significantly elevated Glx levels ( t-test; t=-3.1, P=0.008) within the left DLPFC. CONCLUSIONS. Our results indicate that the prefrontal cortical glutamatergic system is involved in the pathophysiology of acute mania. This may have implications for the treatment of mania." [Abstract]

Dager SR, Friedman SD, Parow A, Demopulos C, Stoll AL, Lyoo IK, Dunner DL, Renshaw PF.
Brain metabolic alterations in medication-free patients with bipolar disorder.
Arch Gen Psychiatry. 2004 May;61(5):450-8.
BACKGROUND: Bipolar disorder (BD) has substantial morbidity and incompletely understood neurobiological underpinnings. OBJECTIVE: To investigate brain chemistry in medication-free individuals with BD. DESIGN: Two-dimensional proton echo-planar spectroscopic imaging (PEPSI) (32 x 32, 1-cm(3) voxel matrix) acquired axially through the cingulate gyrus was used to quantify regional brain chemistry. SETTING: The Center for Anxiety and Depression at the University of Washington in Seattle and the Bipolar Research Programs at McLean Hospital and the Massachusetts General Hospital in Boston. PARTICIPANTS: Thirty-two medication-free outpatients with a diagnosis of BD type I (BDI) or BD type II (BDII), predominantly in a depressed or mixed-mood state, were compared with 26 age- and sex-matched healthy controls. MAIN OUTCOME MEASURES: Tissue type (white and gray) and regional analyses were performed to evaluate distribution of lactate; glutamate, glutamine, and gamma-aminobutyric acid (Glx); creatine and phosphocreatine (Cre); choline-containing compounds (Cho); N-acetyl aspartate; and myo-inositol. Chemical relationships for diagnosis and mood state were evaluated. RESULTS: Patients with BD exhibited elevated gray matter lactate (P =.005) and Glx (P =.007) levels; other gray and white matter chemical measures were not significantly different between diagnostic groups. Isolated regional chemical alterations were found. An inverse correlation between 17-item Hamilton Depression Rating Scale scores and white matter Cre levels was observed for BD patients. CONCLUSIONS: Gray matter lactate and Glx elevations in medication-free BD patients suggest a shift in energy redox state from oxidative phosphorylation toward glycolysis. The possibility of mitochondrial alterations underlying these findings is discussed and may provide a theoretical framework for future targeted treatment interventions. [Abstract]

Castillo, Mauricio, Kwock, Lester, Courvoisie, Helen, Hooper, Stephen R.
Proton MR Spectroscopy in Children with Bipolar Affective Disorder: Preliminary Observations
AJNR Am J Neuroradiol 2000 21: 832-838
"BACKGROUND AND PURPOSE: Bipolar affective disorder (BPAD) can have its onset during childhood, but the diagnosis may be difficult to establish on the basis of clinical findings alone. Our purpose was to determine whether proton MR spectroscopy can be used to identify abnormalities in the brain of children with BPAD. METHODS: Ten children, ages 6 to 12 years, underwent clinical testing to establish the diagnosis of BPAD. After a drug washout period, all patients underwent MR spectroscopy in which a TE of 135 was used along with a single-voxel placement in both frontal and temporal lobes during a single session. Peaks from N-acetylaspartate (NAA), choline (Cho), glutamate/ glutamine (Glu/Gln), and lipids were normalized with respect to the creatine (Cr) peak to obtain ratios of values of peak areas. These data were compared with those obtained in 10 non-age-matched control subjects. To corroborate our data, five children with BPAD also underwent 2D MR spectroscopic studies of the frontal lobes with parameters similar to those used in the single-volume studies. RESULTS: All children with BPAD had elevated levels of Glu/Gln in both frontal lobes and basal ganglia relative to the control group. Children with BPAD had elevated lipid levels in the frontal lobes but not in the temporal lobes. Levels of NAA and Cho were similar for all locations in both groups. Two-dimensional MR spectroscopic studies in five children with BPAD confirmed the presence of elevated lipids in the frontal lobes. CONCLUSION: Our preliminary observations suggest that MR spectroscopy may show abnormalities in children with BPAD not found in unaffected control subjects. It remains to be established whether these abnormalities are a signature of the disease and can be used as a screening test." [Full Text]

Levine J, Panchalingam K, Rapoport A, Gershon S, McClure RJ, Pettegrew JW.
Increased cerebrospinal fluid glutamine levels in depressed patients
Biol Psychiatry. 2000 Apr 1;47(7):586-93.
"BACKGROUND: There is increasing evidence for an association between alterations of brain glutamatergic neurotransmission and the pathophysiology of affective disorders. METHODS: We studied the association between cerebrospinal fluid (CSF) metabolites, including glutamine, in unipolar and bipolar depressed patients versus control subjects using a proton magnetic resonance spectroscopy technique. Cerebrospinal fluid samples were obtained from 18 hospitalized patients with acute unmedicated severe depression without medical problems and compared with those of 22 control subjects. RESULTS: Compared with the control group, the depressed patient group had significantly higher CSF glutamine concentrations, which correlated positively with CSF magnesium levels. CONCLUSIONS: These findings suggest an abnormality of the brain glial-neuronal glutamine/glutamate cycle associated with N-methyl-D-aspartate receptor systems in patients with depression." [Abstract]

McCullumsmith RE, Meador-Woodruff JH.
Striatal excitatory amino acid transporter transcript expression in schizophrenia, bipolar disorder, and major depressive disorder.
Neuropsychopharmacology. 2002 Mar;26(3):368-75.
"Because abnormalities of glutamatergic neurotransmission in psychiatric illness are likely not limited to glutamate receptor expression, we investigated expression of excitatory amino acid transporters (EAATs) in the striatum. The EAATs, normally expressed in both glia (EAAT1 and EAAT2) and neurons (EAAT3 and EAAT4), have previously been implicated in Huntington's disease, amyotrophic lateral sclerosis, and schizophrenia. In this study, we investigated striatal expression of transcripts encoding EAATs in tissue from mood disordered and schizophrenic subjects. With probes designed for the human EAAT1, EAAT2, EAAT3, and EAAT4 transcripts, we performed in situ hybridization and detected decreased expression of EAAT3 and EAAT4 transcripts in the striatum in bipolar disorder. We also detected decreased EAAT3 transcript expression in schizophrenia and decreased EAAT4 transcript expression in major depressive disorder. These results suggest that changes in striatal transporter mRNA expression are restricted to neuronal EAATs and extend the body of evidence implicating abnormal glutamatergic neurotransmission in schizophrenia and mood disorders." [Abstract]

Mundo E, Tharmalingham S, Neves-Pereira M, Dalton EJ, Macciardi F, Parikh SV, Bolonna A, Kerwin RW, Arranz MJ, Makoff AJ, Kennedy JL.
Evidence that the N-methyl-D-aspartate subunit 1 receptor gene (GRIN1) confers susceptibility to bipolar disorder.
Mol Psychiatry 2003 Feb;8(2):241-5
"There is evidence for the involvement of glutamatergic transmission in the pathogenesis of major psychoses. The two most commonly used mood stabilizers (ie lithium and valproate) have been found to act via the N-methyl-D-aspartate receptor (NMDAR), suggesting a specific role of NMDAR in the pathogenesis of bipolar disorder (BP). The key subunit of the NMDAR, named NMDA-1 receptor, is coded by a gene located on chromosome 9q34.3 (GRIN1). We tested for the presence of linkage disequilibrium between the GRIN1 (1001-G/C, 1970-A/G, and 6608-G/C polymorphisms) and BP. A total of 288 DSM-IV Bipolar I, Bipolar II, or schizoaffective disorder, manic type, probands with their living parents were studied. In all, 73 triads had heterozygous parents for the 1001-G/C polymorphism, 174 for the 1970-A/G, and 48 for the 6608-G/C. These triads were suitable for the final analyses, that is, the transmission disequilibrium test (TDT) and the haplotype-TDT. For the 1001-G/C and the 6608-G/C polymorphisms, we found a preferential transmission of the G allele to the affected individuals (chi(2)=4.765, df=1, P=0.030 and chi(2)= 8.395, df=1, P=0.004, respectively). The 1001G-1970A-6608A and the 1001G-1970A-6608G haplotypes showed the strongest association with BP (global chi(2)=14.12, df=4, P=0.007). If these results are replicated there could be important implications for the involvement of the GRIN1 in the pathogenesis of BP. The role of the gene variants in predicting the response to mood stabilizers in BP should also be investigated." [Abstract]

Law AJ, Deakin JF.
Asymmetrical reductions of hippocampal NMDAR1 glutamate receptor mRNA in the psychoses.
Neuroreport. 2001 Sep 17;12(13):2971-4.
"The psychotomimetic properties of NMDA glutamate receptor antagonists suggest there may be disease related changes of this receptor in schizophrenia. Using in situ hybridisation histochemistry (ISHH), we measured mRNA for the obligatory NMDAR1 subunit of the NMDA glutamate receptor in post-mortem samples of hippocampus from schizophrenics, depressives, bipolar patients and normal controls. A significant main effect of diagnosis was observed in the dentate gyrus (ANOVA, p = 0.004) and a trend in the CA3 region (ANOVA, p = 0.06), with all psychiatric groups having reduced NMDAR1 mRNA levels compared to normal controls. In contrast to the affectively ill groups, the reductions in schizophrenics were more pronounced in the left side compared to the right. Expression of poly A mRNA also showed left-sided losses in the dentate gyrus in schizophrenia but reductions in NMDAR1 remained significant when expressed as a ratio of poly A. The findings confirm a recent report of reduced hippocampal NMDAR1 mRNA in schizophrenia. However, our new evidence suggests that this is a feature of both affective and schizophrenic disorders and that schizophrenia is distinguished from the others by left-sided reductions in hippocampal NMDAR1 gene expression." [Abstract]

Scarr E, Pavey G, Sundram S, MacKinnon A, Dean B.
Decreased hippocampal NMDA, but not kainate or AMPA receptors in bipolar disorder.
Bipolar Disord. 2003 Aug;5(4):257-64.
"OBJECTIVES: The purpose of this study was to determine whether there are changes in the density of ionotropic glutamate receptors in the hippocampus of subjects with bipolar disorder. METHODS: Using in situ radioligand binding with semiquantitative autoradiography, we measured the density of [3H]MK-801, [3H]CGP39653, [3H]AMPA and [3H]kainate binding in hippocampi, obtained postmortem, from eight subjects with type 1 bipolar disorder and 8 age- and sex-matched controls. RESULTS: In subjects with bipolar disorder there were significant decreases in the density of [3H]MK-801 binding in the Cornu Ammonis (CA) 3 (mean +/- SEM; 108.8 +/- 12.2 versus 166.2 +/- 18.0 fmol/mg ETE, p < 0.005) as well as the pyramidal (102.8 +/- 9.2 versus 136.6 +/- 11.2 fmol/mg ETE, p < 0.05) and polymorphic (21.73 +/- 6.5 versus 53.26 +/- 11.6 fmol/mg ETE, p < 0.05) layers of the subiculum. In addition, two-way analysis of variance (ANOVA) revealed a decrease in the density of [3H]CGP39653 binding across the hippocampal formation in bipolar subjects, which did not reach significance in any subregion. There were no changes in the densities of [3H]AMPA or [3H]kainate binding in these subjects. CONCLUSIONS: [3H]CGP39653 and [3H]MK-801 bind to the glutamate binding site and open ion channel of the n-methyl-d-aspartate (NMDA) receptor, respectively. Therefore, these data suggest that there is a decrease in the number of open ion channels associated with no significant change in the apparent density of NMDA receptors in regions of the hippocampus from subjects with bipolar disorder." [Abstract]

Clinton SM, Meador-Woodruff JH.
Abnormalities of the NMDA Receptor and Associated Intracellular Molecules in the Thalamus in Schizophrenia and Bipolar Disorder.
Neuropsychopharmacology. 2004 Jul;29(7):1353-62.
Several lines of investigation support a hypothesis of glutamatergic dysfunction in schizophrenia, including our recent reports of altered NMDA receptor subunit and associated intracellular protein transcripts in the thalamus of elderly patients with schizophrenia. In the present study, we used in situ hybridization to measure the expression of NMDA subunits (NR1, NR2A-D), and associated intracellular proteins (NF-L, PSD95, and SAP102) in a second, younger cohort from the Stanley Foundation Neuropathology Consortium, which included patients with both schizophrenia and affective disorders. We wanted to determine whether glutamatergic abnormalities in the thalamus in schizophrenia are present at younger ages, and whether these abnormalities occur in other psychiatric illnesses. In the present work, we observed increased expression of NMDA NR2B subunit transcripts, and decreased expression of all three associated postsynaptic density protein transcripts in schizophrenia. We also found evidence of glutamatergic dysfunction in the thalamus in affective disorders, particularly in bipolar disorder. In particular, we found decreased NF-L, PSD95, and SAP102 transcripts in bipolar disorder, and decreased SAP102 levels in major depression. Interestingly, one of the most consistent findings across diagnostic groups was an abnormality of intracellular signaling molecules that are linked to the NMDA receptor, rather than changes in the receptor subunits themselves. PSD95 and similar scaffolding molecules link the NMDA receptor with intracellular enzymes that mediate signaling, and also provide a physical link between different neurotransmitter systems to coordinate and integrate information from multiple effector systems. Abnormalities of PSD95-like molecules and other intracellular signaling machinery may contribute to dysregulated communication between multiple neurotransmitter systems (such as glutamatergic and dopaminergic systems) that are potentially involved in the neurobiology of schizophrenia and affective disorders. [Abstract]

Schiffer HH.
Glutamate receptor genes: susceptibility factors in schizophrenia and depressive disorders?
Mol Neurobiol. 2002 Apr;25(2):191-212.
"Schizophrenia, depression, and bipolar disorder are three major neuropsychiatric disorders that are among the leading causes of disability and have enormous economic impacts on our society. Although several neurotransmitter systems have been suggested to play a role in their etiology, we still have not identified any gene or molecular mechanism that might lead to genetic susceptibility for or protection against these neuropsychiatric disorders. The glutamatergic receptor system, and in particular the N-methyl-D-aspartate (NMDA) receptor complex, has long been implicated in their etiology. I review the current molecular evidence that supports a critical role for the glutamatergic receptor system in schizophrenia and the potential involvement of this receptor system in depression and bipolar disorder. It is likely that mutations in glutamate receptor genes might alter the risk of developing one of these disorders. Potential future research directions designed to identify these mutations and to elucidate their effect on mental health will be discussed." [Abstract]

Meador-Woodruff JH, Hogg AJ Jr, Smith RE.
Striatal ionotropic glutamate receptor expression in schizophrenia, bipolar disorder, and major depressive disorder.
Brain Res Bull. 2001 Jul 15;55(5):631-40.
"Abnormalities of the ionotropic glutamate receptors (N-methyl-D-aspartate, alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid [AMPA], and kainate) have been reported in the brain in schizophrenia, although in complex, region-specific patterns. While limbic cortex and medial temporal lobe structures have been most often studied in psychiatric illnesses, glutamate receptors are expressed in other brain regions associated with limbic circuitry, especially the striatum. In this study, we have determined striatal ionotropic glutamate receptor expression in brains from persons with schizophrenia, bipolar disorder, major depression, and a comparison group, using samples from the Stanley Foundation Neuropathology Consortium. We have determined the expression of these receptors at multiple levels of gene expression by using both in situ hybridization and receptor autoradiography. The expression of nearly all of these molecules was not different in these psychiatric conditions. The only significant changes noted were NR2D and gluR1 transcripts, and [(3)H]AMPA binding. This is the first comprehensive study of striatal ionotropic glutamate receptor expression in schizophrenia and affective disorders, and suggests that there are minimal changes in these receptors in this region of the brain in these illnesses." [Abstract]

Benes FM, Todtenkopf MS, Kostoulakos P.
GluR5,6,7 subunit immunoreactivity on apical pyramidal cell dendrites in hippocampus of schizophrenics and manic depressives.
Hippocampus. 2001;11(5):482-91.
"Recent postmortem studies have suggested that changes in the regulation of kainate-sensitive glutamate receptors (kainate receptors) in the hippocampus may play a role in schizophrenia. To explore this possibility further, the distribution of immunoreactivity (IR) for the GluR5,6,7 subunits of the KR was assessed in a cohort consisting of 15 normal controls, 15 schizophrenics, and 9 manic depressives matched for age and postmortem interval (PMI). Cross sections of hippocampus showed abundant GluR5,6,7-IR on apical dendrites of pyramidal neurons in the stratum radiatum and stratum moleculare. In normal controls, both the numerical and length density of IR dendrites were much higher in sector CA2 than in sectors CA3 or CA1. When data for the individual groups were separately examined, the schizophrenics showed a 30-35% reduction in the density of GluR5,6,7-IR dendrites found in both stratum radiatum and stratum moleculare of sectors CA3 and CA2, as well as proximal and middle portions of CA1. In CA2, the magnitude of this decrease in schizophrenia was 2.5 times larger than that seen in any of the other sectors. For the manic depressive group, no significant differences were observed in any sectors or laminae examined. The potential confounding effects of either age, PMI, or neuroleptic exposure do not explain the reduced density of IR dendrites detected in the schizophrenic group. Taken together, the preferential reduction of GluR5,6,7-IR observed on apical dendrites of pyramidal neurons is consistent with a functional downregulation of the kainate receptor in the hippocampus of schizophrenic brain." [Abstract]

Kalkman HO, Loetscher E.
GAD(67): the link between the GABA-deficit hypothesis and the dopaminergic- and glutamatergic theories of psychosis.
J Neural Transm. 2003 Jul;110(7):803-12.
"Decreases in the 67 kDa isoenzyme of brain glutamic acid decarboxylase (GAD(67)) expression have been consistently found in patients with bipolar disorder and schizophrenia. In animals GAD(67) expression is diminished by chronic, but not acute stimulation of dopamine D(2) receptors and by short-term blockade of NMDA receptors. In contrast, chronic treatment with D(2) receptor antagonists enhances GAD(67) expression. Thus, antipsychotic treatment cannot explain the reduction in GAD(67) levels in patients with psychotic disorders. Rather, pathophysiological findings such as reduced viability of cortical glutamatergic neurones (in schizophrenia) or enhanced dopamine sensitivity (in bipolar disorder) might explain the observed reduction in GAD(67). Since reduction in GAD(67) expression leads to reduced levels of GABA, the GABAergic inhibitory control over glutamatergic cells is reduced. Psychosis could result from AMPA receptor activation caused by overactivity of the glutamatergic system. GAD(67) levels would thus be a surrogate marker for psychosis liability. Pharmacological principles that raise GAD(67) expression levels could represent novel targets for antipsychotic therapy." [Abstract]
Du J, Gray NA, Falke CA, Chen W, Yuan P, Szabo ST, Einat H, Manji HK.
Modulation of synaptic plasticity by antimanic agents: the role of AMPA glutamate receptor subunit 1 synaptic expression.
J Neurosci. 2004 Jul 21;24(29):6578-89.
Increasing data suggest that impairments of cellular plasticity underlie the pathophysiology of bipolar disorder. In this context, it is noteworthy that AMPA glutamate receptor trafficking regulates synaptic plasticity, effects mediated by signaling cascades, which are targets for antimanic agents. The present studies were undertaken to determine whether two clinically effective, but structurally highly dissimilar, antimanic agents lithium and valproate regulate synaptic expression of AMPA receptor subunit glutamate receptor 1 (GluR1). Chronic (but not acute) treatment of rats with therapeutically relevant concentrations of lithium or valproate reduced hippocampal synaptosomal GluR1 levels. The reduction in synaptic GluR1 by lithium and valproate was attributable to a reduction of surface GluR1 distribution onto the neuronal membrane as demonstrated by three independent assays in cultured hippocampal neurons. Furthermore, these agents induced a decrease in GluR1 phosphorylation at a specific PKA site (GluR1p845), which is known to be critical for AMPA receptor insertion. Sp-cAMP treatment reversed the attenuation of phosphorylation by lithium and valproate and also brought GluR1 back to the surface, suggesting that phosphorylation of GluR1p845 is involved in the mechanism of GluR1 surface attenuation. In addition, GluR1p845 phosphorylation also was attenuated in hippocampus from lithium- or valproate-treated animals in vivo. In contrast, imipramine, an antidepressant that can trigger manic episodes, increased synaptic expression of GluR1 in hippocampus in vivo. These studies suggest that regulation of glutamatergically mediated synaptic plasticity may play a role in the treatment of bipolar disorder and raise the possibility that agents more directly affecting synaptic GluR1 may represent novel therapies for this devastating illness.
[Abstract]
Woo TU, Walsh JP, Benes FM.
Density of glutamic acid decarboxylase 67 messenger RNA-containing neurons that express the N-methyl-D-aspartate receptor subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder.
Arch Gen Psychiatry. 2004 Jul;61(7):649-57.
BACKGROUND: Disturbances of gamma-aminobutyric acid interneurons in the cerebral cortex contribute to the pathophysiology of schizophrenia and bipolar disorder. The activity of these neurons is, in turn, modulated by glutamatergic inputs furnished by pyramidal neurons. OBJECTIVE: To test the hypothesis that glutamatergic inputs onto gamma-aminobutyric acid interneurons via the N-methyl-d-aspartate (NMDA) receptor are altered in the anterior cingulate cortex in schizophrenia and bipolar disorder. DESIGN: A double in situ hybridization technique was used to simultaneously label the messenger RNA (mRNA) for the NMDA NR(2A) subunit with (35)sulfur and the mRNA for the 67-kDa isoform of the gamma-aminobutyric acid synthesizing enzyme glutamic acid decarboxylase (GAD(67)) with digoxigenin. SETTING: Postmortem human brain studies. PARTICIPANTS: We studied 17 subjects with schizophrenia, 17 subjects with bipolar disorder, and 17 normal control subjects. RESULTS: The density of all GAD(67) mRNA-containing neurons was decreased by 53% and 28%, in layers 2 and 5, respectively, in subjects with schizophrenia, whereas in subjects with bipolar disorder there was a 35% reduction in layer 2 only. For GAD(67) mRNA-containing neurons that co-expressed NR(2A)mRNA, their numerical density was decreased by 73% and 52%, in layers 2 and 5, respectively, in subjects with schizophrenia and by 60% in layer 2 in those with bipolar disorder. In the schizophrenia group, the density of the GAD(67)mRNA-containing neurons that did not co-express NR(2A)mRNA was also decreased by 42% in layer 2. In both disease groups, the expression level of NR(2A)mRNA in GAD(67) mRNA-containing cells was unaltered. CONCLUSIONS: The density of gamma-aminobutyric acid interneurons that express the NMDA NR(2A)subunit appears to be decreased in schizophrenia and bipolar disorder. Future studies will address whether subpopulations of these neurons may be differentially affected in the 2 conditions. [Abstract]

Heckers S, Stone D, Walsh J, Shick J, Koul P, Benes FM.
Differential hippocampal expression of glutamic acid decarboxylase 65 and 67 messenger RNA in bipolar disorder and schizophrenia.
Arch Gen Psychiatry. 2002 Jun;59(6):521-9.
"BACKGROUND: Expression of messenger RNA (mRNA) for the gamma-aminobutyric acid (GABA)-synthesizing enzyme, glutamic acid decarboxylase (GAD), in the prefrontal cortex and the number of GABAergic neurons in the hippocampus are reduced in schizophrenia and bipolar disorder. We tested the hypothesis that the expression of the 2 isoforms, one 65 kd (GAD(65)) and the other 67 kd (GAD(67)), is differentially affected in the hippocampus in schizophrenia and bipolar disorder. METHODS: Hippocampal sections from 15 subjects in 3 groups (control subjects and subjects with schizophrenia and bipolar disorder) were studied using an in situ hybridization protocol with sulfur 35-labeled complementary riboprobes for GAD(65) and GAD(67) mRNA. Emulsion-dipped slides were analyzed for the density of GAD mRNA-positive neurons in 4 sectors of the hippocampus and for the cellular expression level of both GAD mRNAs. RESULTS: The density of GAD(65) and GAD(67) mRNA-positive neurons was decreased by 45% and 43%, respectively, in subjects with bipolar disorder, but only 14% and 4%, respectively, in subjects with schizophrenia. The decreased density of GAD(65) mRNA-positive neurons in subjects with bipolar disorder was significant in sectors CA2/3 and dentate gyrus, and that of GAD(67) mRNA-positive neurons was significant in CA4, but not other hippocampal sectors. Cellular GAD(65) mRNA expression was significantly decreased in subjects with bipolar disorder, particularly in CA4, but not in schizophrenic subjects. Cellular GAD(67) mRNA expression was normal in both groups. CONCLUSION: We have found a region-specific deficit of GAD(65) and GAD(67) mRNA expression in bipolar disorder." [Abstract]
Guidotti A, Auta J, Davis JM, Di-Giorgi-Gerevini V, Dwivedi Y, Grayson DR, Impagnatiello F, Pandey G, Pesold C, Sharma R, Uzunov D, Costa E, DiGiorgi Gerevini V.
Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study.
Arch Gen Psychiatry. 2000 Nov;57(11):1061-9.
"BACKGROUND: Reelin (RELN) is a glycoprotein secreted preferentially by cortical gamma-aminobutyric acid-ergic (GABAergic) interneurons (layers I and II) that binds to integrin receptors located on dendritic spines of pyramidal neurons or on GABAergic interneurons of layers III through V expressing the disabled-1 gene product (DAB1), a cytosolic adaptor protein that mediates RELN action. To replicate earlier findings that RELN and glutamic acid decarboxylase (GAD)(67), but not DAB1 expression, are down-regulated in schizophrenic brains, and to verify whether other psychiatric disorders express similar deficits, we analyzed, blind, an entirely new cohort of 60 postmortem brains, including equal numbers of patients matched for schizophrenia, unipolar depression, and bipolar disorder with nonpsychiatric subjects. METHODS: Reelin, GAD(65), GAD(67), DAB1, and neuron-specific-enolase messenger RNAs (mRNAs) and respective proteins were measured with quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) or Western blot analyses. Reelin-positive neurons were identified by immunohistochemistry using a monoclonal antibody. RESULTS: Prefrontal cortex and cerebellar expression of RELN mRNA, GAD(67) protein and mRNA, and prefrontal cortex RELN-positive cells was significantly decreased by 30% to 50% in patients with schizophrenia or bipolar disorder with psychosis, but not in those with unipolar depression without psychosis when compared with nonpsychiatric subjects. Group differences were absent for DAB1,GAD(65) and neuron-specific-enolase expression implying that RELN and GAD(67) down-regulations were unrelated to neuronal damage. Reelin and GAD(67) were also unrelated to postmortem intervals, dose, duration, or presence of antipsychotic medication. CONCLUSIONS: The selective down-regulation of RELN and GAD(67) in prefrontal cortex of patients with schizophrenia and bipolar disorder who have psychosis is consistent with the hypothesis that these parameters are vulnerability factors in psychosis; this plus the loss of the correlation between these 2 parameters that exists in nonpsychotic subjects support the hypothesis that these changes may be liability factors underlying psychosis." [Abstract]
Tremolizzo L, Carboni G, Ruzicka WB, Mitchell CP, Sugaya I, Tueting P, Sharma R, Grayson DR, Costa E, Guidotti A.
An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability.
Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):17095-100. Epub 2002 Dec 12.
"Reelin and glutamic acid decarboxylase (GAD)67 expressed by cortical gamma-aminobutyric acid-ergic interneurons are down-regulated in schizophrenia. Because epidemiological studies of schizophrenia fail to support candidate gene haploinsufficiency of Mendelian origin, we hypothesize that epigenetic mechanisms (i.e., cytosine hypermethylation of CpG islands present in the promoter of these genes) may be responsible for this down-regulation. Protracted l-methionine (6.6 mmolkg for 15 days, twice a day) treatment in mice elicited in brain an increase of S-adenosyl-homocysteine, the processing product of the methyl donor S-adenosyl-methionine, and a marked decrease of reelin and GAD67 mRNAs in both WT and heterozygous reeler mice. This effect of l-methionine was associated with an increase in the number of methylated cytosines in the CpG island of the reelin promoter region. This effect was not observed for GAD65 or neuronal-specific enolase and was not replicated by glycine doses 2-fold greater than those of l-methionine. Prepulse inhibition of startle declined at a faster rate as the prepulsestartle interval increased in mice receiving l-methionine. Valproic acid (2 mmolkg for 15 days, twice a day) reverted l-methionine-induced down-regulation of reelin and GAD67 in both WT and heterozygous reeler mice, suggesting an epigenetic action through the inhibition of histone deacetylases. The same dose of valproate increased acetylation of histone H3 in mouse brain nearly 4-fold. This epigenetic mouse model may be useful in evaluating drug efficacy on schizophrenia vulnerability. Hence the inhibition of histone deacetylases could represent a pharmacological intervention mitigating epigenetically induced vulnerability to schizophrenia in individuals at risk." [Full Text]
Ketter TA, Wang PW.
The emerging differential roles of GABAergic and antiglutamatergic agents in bipolar disorders.
J Clin Psychiatry. 2003;64 Suppl 3:15-20.
"Treatment options to relieve the diverse symptoms encountered in patients with bipolar disorders include not only mood stabilizers, but also anxiolytics, new anticonvulsants, antidepressants, and antipsychotics. These agents have widely varying mechanisms of action, which could contribute to the heterogeneity of clinical effects seen in practice. Several of these medications, especially those with anticonvulsant effects, enhance gamma-aminobutyric acid (GABA) inhibitory neurotransmission and/or attenuate glutamate excitatory neurotransmission. We review the efficacy and tolerability of these diverse treatment options in bipolar disorders and explore possible relationships between clinical effects and GABAergic and antiglutamatergic mechanisms of action." [Abstract]
DD DD, Marek GJ.
Preclinical pharmacology of mGlu2/3 receptor agonists: novel agents for schizophrenia?
Curr Drug Target CNS Neurol Disord. 2002 Apr;1(2):215-25.
"Agonists for mGlu2/3 receptors decrease the evoked release of glutamate at certain (ie. forebrain / limbic) glutamatergic synapses, indicating that the functional role of mGlu2 and/or mGlu3 receptors is to suppress glutamate excitations. This offers a mechanism for dampening glutamate excitation under pathological states resulting from excessive glutamate release. Based, in part, on the psychotomimetic actions of phencyclidine (PCP)- like drugs, excessive or pathological glutamate release has been implicated in a number of clinical conditions including psychosis. With this in mind, the pharmacology of multiple mGlu2/3 receptor agonists have been investigated in PCP treated rats. Agonists for mGlu2/3 receptors such as LY354740 and LY379268 have been shown to block certain behavioral responses to PCP in rats. The effects of mGlu2/3 agonists on PCP-induced behaviors are blocked by a low doses of a selective mGlu2/3 receptor antagonist, indicating that these actions are mediated via mGlu2/3 receptors. In addition, mGlu2/3 agonists potently suppress glutamate release in rat prefrontal cortex, as reflected by excitatory post-synaptic potentials (EPSPs) induced by serotonin (5-HT) acting on 5HT(2A) receptors. These actions of LY354740 and LY379268 are also blocked by a selective mGlu2/3 antagonist. Atypical antipsychotic drugs such as clozapine also suppress 5-HT-induced EPSPs in this brain region, thus suggesting a common pathway for the actions of atypical antipsychotic drugs and mGlu2/3 receptor agonists. As glutamatergic dysfunction has been implicated in psychotic states and possibly in the etiology of schizophrenia, clinical studies with mGlu2/3 agonists may be warranted to further explore the validity of the glutamatergic hypothesis of schizophrenia." [Abstract]
Brody SA, Geyer MA, Large CH.
Lamotrigine prevents ketamine but not amphetamine-induced deficits in prepulse inhibition in mice.
Psychopharmacology (Berl). 2003 Apr 16 [Epub ahead of print].
"RATIONALE. Lamotrigine, a broad-spectrum anticonvulsant known to block brain sodium channels, is effective in the treatment of persons with bipolar disorder, perhaps by virtue of its ability to reduce glutamate release. Furthermore, lamotrigine decreases the perceptual abnormalities produced by the N-methyl- d-aspartate (NMDA) antagonist ketamine in humans, similar to the effects of the atypical antipsychotic clozapine. Acutely manic bipolar patients, like persons with schizophrenia, Tourette's, and obsessive compulsive disorder, exhibit decreases in sensorimotor gating, as measured by prepulse inhibition of the startle response (PPI). OBJECTIVE. We assessed the ability of lamotrigine to reduce the PPI-disruptive effects of ketamine and the dopaminergic agent amphetamine in two inbred mouse strains, C57BL/6J and 129SvPasIco. METHODS. Mice were tested in a standard PPI paradigm after administration of lamotrigine (0, 6.7, 13, or 27 mg/kg) or a combination of lamotrigine (27 mg/kg) and either d-amphetamine (10 mg/kg) or ketamine (100 mg/kg). RESULTS. In the 129SvPasIco mice, lamotrigine reversed the ketamine-induced PPI deficit, without altering PPI in control mice. In C57BL/6J mice, however, 27 mg/kg lamotrigine generally increased PPI in both control and ketamine-treated mice. Lamotrigine did not ameliorate the amphetamine-induced PPI deficit in either strain. CONCLUSIONS. In conclusion, lamotrigine can increase PPI on its own and prevent ketamine-induced, but not amphetamine-induced, disruptions of PPI. These results suggest that lamotrigine may exert its effects on PPI through the glutamatergic system." [Abstract]
John F. Dixon, and Lowell E. Hokin
Lithium acutely inhibits and chronically up-regulates and stabilizes glutamate uptake by presynaptic nerve endings in mouse cerebral cortex
PNAS 95: 8363-8368, 1998.
"We previously reported that lithium stimulated extracellular glutamate accumulation in monkey and mouse cerebrocortical slices. We report here that this is caused by lithium-induced inhibition of glutamate uptake into the slice. Glutamate release was amplified 5-fold over inhibition of uptake. When the effects of lithium and the specific glutamate transporter inhibitors, L-trans-pyrrolidine-2, 4-dicarboxylic acid and dihydrokainic acid, were plotted as glutamate accumulation vs. inhibition of glutamate uptake, the plots were superimposable. This finding strongly indicates that lithium-induced glutamate accumulation is caused entirely by inhibition of uptake. With cerebrocortical synaptosomes, inhibition of glutamate uptake was greater than in slices, suggesting that presynaptic nerve endings are the primary site of inhibition of uptake by lithium. Inhibition of uptake was caused by a progressive lowering of Vmax, as the lithium concentration was increased, whereas the Km remained constant, indicating that lithium inhibited the capacity of the transporter but not its affinity. Chronic treatment of mice with lithium, achieving a blood level of 0.7 mM, which is on the low side of therapeutic, up-regulated synaptosomal uptake of glutamate. This would be expected to exert an antimanic effect. Lithium is a mood stabilizer, dampening both the manic and depressive phases of bipolar disorder. Interestingly, although the uptake of glutamate varied widely in individual control mice, uptake in lithium-treated mice was stabilized over a narrow range (variance in controls, 0.423; in lithium treated, 0.184)." [Full Text]
Bown CD, Wang JF, Young LT.
Attenuation of N-methyl-D-aspartate-mediated cytoplasmic vacuolization in primary rat hippocampal neurons by mood stabilizers.
Neuroscience. 2003;117(4):949-55.
"Recent post-mortem and brain imaging studies suggest that decreased neuronal and glial densities may account for cell loss in vulnerable brain regions such as the hippocampus and the frontal cortex in patients with bipolar disorder. Investigations into the mechanisms of action of mood stabilizers suggest that these drugs may regulate the expression of neuroprotective genes and protect against excitotoxicity. In this study, we characterized the ultrastructural appearance of rat hippocampal neurons pretreated with mood stabilizers and then exposed to the glutamate receptor agonist N-methyl-D-aspartate. Using transmission electron microscopy we found that rat hippocampal neurons exposed to 0.5 mM N-methyl-D-aspartate for 10 min produced more cytoplasmic vacuolization than in control neurons. Chronic treatment with mood stabilizers, lithium, valproate or carbamazepine for 7 days at therapeutically relevant concentrations fully attenuated N-methyl-D-aspartate-mediated cytoplasmic vacuolization. These results suggest that inhibition of neurotoxicity may be involved in the action of mood stabilizers." [Abstract]
Wood GE, Young LT, Reagan LP, Chen B, McEwen BS.
Stress-induced structural remodeling in hippocampus: prevention by lithium treatment.
Proc Natl Acad Sci U S A. 2004 Mar 16;101(11):3973-8. Epub 2004 Mar 04.
Chronic restraint stress, psychosocial stress, as well as systemic or oral administration of the stress-hormone corticosterone induces a morphological reorganization in the rat hippocampus, in which adrenal steroids and excitatory amino acids mediate a reversible remodeling of apical dendrites on CA3 pyramidal cell neurons of the hippocampus. This stress-induced neuronal remodeling is accompanied also by behavioral changes, some of which can be prevented with selective antidepressant and anticonvulsive drug treatments. Lithium is an effective treatment for mood disorders and has neuroprotective effects, which may contribute to its therapeutic properties. Thus, we wanted to determine whether lithium treatment could prevent the effects of chronic stress on CA3 pyramidal cell neuroarchitecture and the associated molecular and behavioral measures. Chronic lithium treatment prevented the stress-induced decrease in dendritic length, as well as the stress-induced increase in glial glutamate transporter 1 (GLT-1) mRNA expression and the phosphorylation of cAMP-response element binding in the hippocampus. Lithium treatment, however, did not prevent stress effects on behavior in the open field or the plus-maze. These data demonstrate that chronic treatment with lithium can protect the hippocampus from potentially deleterious effects of chronic stress on glutamatergic activation, which may be relevant to its therapeutic efficacy in the treatment of major depressive disorder and bipolar disorder. [Abstract]

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Recent Bipolar Disorder & Glutamate Research
1) Stevens J, Bies RR, Shekhar A, Anand A
Bayesian Model of HDRS with Memantine Augmentation in Bipolar Depression.
Br J Clin Pharmacol. 2012 Jul 30;
AIM: Presynaptic- and postsynaptic glutamatergic modulation is associated with anti-depressant activity that takes several weeks to reach a maximal full effect. Limiting mood elevating effects after single drug administration may be the result of compensatory synaptic processes. Therefore, using augmentation treatment with agents having presynaptic- and postsynaptic effects on the glutamatergic system, this study aims to evaluate the effect of augmentation therapy on the rate of change in mood elevation in patients with bipolar depression. METHODS: In a pilot study, 29 bipolar depression outpatients on a stable lamotrigine dose regimen received placebo or memantine pills daily (titrated up by 5 mg per week to 20 mg) in a randomized, double blind, parallel group, 8-week study. Patients were evaluated weekly using the 17-item Hamilton Depression Rating Score (HDRS) and all data were analyzed simultaneously. Linear-, exponential-, maximal effect-, Gompertz- and inverse Bateman functions were evaluated using a Bayesian approach population pharmacodynamic model framework. In these models, differences in parameters were examined across the memantine and placebo augmentation groups. RESULTS: A Gompertz function with a treatment switch on the parameter describing the speed of HDRS (? (95% confidence interval)) decline best described the data (?memantine = 1.8 (0.9-3.6), ?placebo = 1.2 (0.5-3.5)). Between subject variability was identified on baseline HDRS (2.9 (1.5-4.4)) and amplitude of score improvement (4.3 (2.7-6.5)). CONCLUSIONS: This pharmacodynamic approach identified an increased speed of response after memantine augmentation, compared to placebo augmentation in bipolar depression patients. [PubMed Citation] [Order full text from Infotrieve]

2) Ha CM, Park D, Han JK, Jang JI, Park JY, Hwang EM, Seok H, Chang S
Calcyon forms a novel ternary complex with dopamine D1 receptor through PSD-95 and plays a role in dopamine receptor internalization.
J Biol Chem. 2012 Jul 26;
Calcyon, once known for interacting directly with the dopamine D1 receptor (D1DR), is implicated in various neuropsychiatric disorders including schizophrenia, bipolar disorder and ADHD. Although its direct interaction with D1DR has been shown to be misinterpreted, it still plays important roles in the D1DR signaling. Here, we found that calcyon interacts with the PSD-95 and subsequently forms a ternary complex with D1DR through PSD-95. Calcyon is phosphorylated on Ser169 by the PKC activator PMA or by the D1DR agonist SKF81297, and its phosphorylation increases its association with PSD-95 and recruitment to the cell surface. Interestingly, the internalization of D1DR at the cell surface was enhanced by PMA and SKF81297 in the presence of calcyon, but not in the presence of its S169A phospho-deficient mutant, suggesting that the phosphorylation of caclyon and the internalization of the surface D1DR are tightly correlated. Our results suggest that calcyon regulates D1DR trafficking by forming a ternary complex with D1DR through PSD-95 and thus, possibly linking a glutamatergic and dopamine receptor signalings. This also raises the possibility that a novel ternary complex could represent a potential therapeutic target for the modulation of related neuropsychiatric disorders. [PubMed Citation] [Order full text from Infotrieve]

3) Gigante AD, Bond DJ, Lafer B, Lam RW, Young LT, Yatham LN
Brain glutamate levels measured by magnetic resonance spectroscopy in patients with bipolar disorder: a meta-analysis.
Bipolar Disord. 2012 Aug;14(5):478-87.
Gigante AD, Bond DJ, Lafer B, Lam RW, Young LT, Yatham LN. Brain glutamate levels measured by magnetic resonance spectroscopy in patients with bipolar disorder: a meta-analysis. Bipolar Disord 2012: 14: 478-487. � 2012 The Authors. Journal compilation � 2012 John Wiley & Sons A/S. Objectives:? Bipolar disorder (BD) is a common and highly disabling disease characterized by substantial cognitive and functional impairment. The exact neurobiological mechanisms underlying the expression of symptoms in this condition remain unknown but there is growing evidence that glutamate might play an important role. Using proton magnetic resonance spectroscopy ((1) H-MRS), a number of studies have examined brain glutamate/glutamine levels in patients with bipolar disorder, but they have produced conflicting results. The objective of this paper was to conduct a systematic review and meta-analysis of the literature on brain glutamate/glutamine in BD as measured by (1) H-MRS. Methods:? A Medline search for the period January 1980-April 2010 was conducted to identify published studies that used (1) H-MRS to measure glutamate?+?glutamine (Glx), the Glx/creatine (Cr) ratio, glutamate (Glu), or the Glu/Cr ratio in any brain region in adult or child/adolescent patients with BD and healthy subjects. A meta-analysis of the pooled data was conducted. Results:? BD patients were found to have increased Glx compared to healthy subjects when all brain areas were combined. This finding remained true in medicated and non-medicated patients, and in frontal brain areas in adults. There was a non-significant trend (p?=?0.09) for an increase in whole-brain Glx/Cr and Glu in patients compared with healthy subjects. No significant difference was found in Glu/Cr. Conclusions:? The results of this meta-analysis suggest that brain Glx levels are elevated in BD patients and support the idea that glutamate might play an important role in the pathophysiology of BD. [PubMed Citation] [Order full text from Infotrieve]

4) Lee A, Anderson AR, Barnett NL, Stevens MG, Pow DV
Alternate splicing and expression of the glutamate transporter EAAT5 in the rat retina.
Gene. 2012 Jul 20;
Excitatory amino acid transporter 5 (EAAT5) is an unusual glutamate transporter that is expressed in the retina, where it is localised to two populations of glutamatergic neurons, namely the bipolar neurons and photoreceptors. EAAT5 exhibits two distinct properties, acting both as a slow glutamate transporter and as a glutamate-gated inhibitory receptor. The latter property is attributable to a co-associated chloride conductance. EAAT5 has previously been thought to exist only as a full-length form. We now demonstrate by PCR cloning and sequencing, the presence of five novel splice variant forms of EAAT5 which skip either partial or complete exons in the rat retina. Furthermore, we demonstrate that each of these variants is expressed at the protein level as assessed by Western blotting using splice-specific antibodies that we have generated. We conclude that EAAT5 exists in multiple spliced forms, and propose, based upon retention or absence of key structural features, that these variant forms may potentially exhibit distinct properties relative to the originally described form of EAAT5. [PubMed Citation] [Order full text from Infotrieve]

5) Chang WC, Lee CM, Shyu BC
Temporal and spatial dynamics of thalamus-evoked activity in the anterior cingulate cortex.
Neuroscience. 2012 Jul 16;
In the present study, multielectrode array (MEA) recording was used to illustrate the spatial-temporal progression of anterior cingulate cortex (ACC) activity following stimulation of the thalamus in a thalamocingulate pathway-preserved slice. The MEA was placed under the slice that contained the ACC, and 60 channels of extracellular local field potentials evoked by bipolar electrical stimulation within the thalamus were analyzed. Several distinct thalamic-evoked responses were identified. The early negative component (N1; amplitude, -35.7 � 5.9 ?V) emerged in layer VI near the cingulum 8.4 � 0.5 ms after stimulation. N1 progressed upward to layers V and II/III in a lateral-to-medial direction. Subsequently, a positive component (P; amplitude, 27.0 � 3.2 ?V) appeared 12.0 � 0.6 ms after stimulation in layer VI. At 26.8 � 1.1 ms, a second negative component (N2; amplitude, -20.9 � 2.7 ?V) became apparent in layers II/III and V, followed by a more ventrolateral component (N3; amplitude, -18.9 � 2.9 ?V) at 42.8 � 2.6 ms. These two late components spread downward to layer VI in a medial-to-lateral direction. The trajectory paths of the evoked components were consistently represented with varied medial thalamic stimulation intensities and sites. Both AMPA/kainate and N-methyl-D-aspartate-type glutamate receptors involved in monosynaptic and polysynaptic transmission participated in this thalamocortical pathway. Morphine mainly diminished the two negative synaptic components, and this suppressive effect was reversed by naloxone. The present study confirmed that functional thalamocingulate activity was preserved in the brain-slice preparation. The thalamus-evoked responses were activated and progressed along a deep surface-deep trajectory loop across the ACC layers. Glutamatergic neurotransmitters were crucially involved in information processing. Opioid interneurons may play a modulatory role in regulating the signal flows in the cingulate cortex. [PubMed Citation] [Order full text from Infotrieve]

6) Dickerson F, Stallings C, Vaughan C, Origoni A, Khushalani S, Yolken R
Antibodies to the glutamate receptor in mania.
Bipolar Disord. 2012 Aug;14(5):547-53.
Dickerson F, Stallings C, Vaughan C, Origoni A, Khushalani S, Yolken R. Antibodies to the glutamate receptor in mania. Bipolar Disord 2012: 14: 547-553. � 2012 The Authors.Journal compilation � 2012 John Wiley & Sons A/S. Background:? There is evidence that the glutamatergic system is involved in the pathophysiology of mania. Antibodies to the NR2 subunits of the N-methyl-D-aspartate (NMDA) receptor have been shown to adversely affect glutamate functioning. Methods:? We measured serum antibodies to the NR2 peptide of the NMDA receptor in 60 individuals with different subtypes of mania, including schizoaffective cases, who were assessed at up to three time points. We also measured these antibodies in 295 individuals in other psychiatric groups and in 170 non-psychiatric controls. NR2 antibody levels were compared among groups by multivariate analyses and within the mania group by repeated measures analysis of variance. Results:? Individuals with mania had increased levels of antibodies to the NR2 peptide compared to levels in non-psychiatric controls when measured at the time of admission (t?=?2.99, p?=?0.003) and the time of evaluation (t?=?2.57, p?=?0.010), but not at follow-up six?months later. The levels of antibodies in individuals in other psychiatric groups did not differ significantly from the levels measured in the control population. Within the mania group, there was a significant decrease in antibody levels over the three time points of the study (F?=?5.4, df?=?2, p?=?0.0067). Conclusions:? NR2 antibodies are elevated during the acute phase of mania but not at follow-up. Our findings support a role for antibodies to the NMDA receptor in the pathogenesis of acute mania. [PubMed Citation] [Order full text from Infotrieve]

7) Strawn JR, Patel NC, Chu WJ, Lee JH, Adler CM, Kim MJ, Bryan HS, Alfieri DC, Welge JA, Blom TJ, Nandagopal JJ, Strakowski SM, DelBello MP
Glutamatergic effects of divalproex in adolescents with mania: a proton magnetic resonance spectroscopy study.
J Am Acad Child Adolesc Psychiatry. 2012 Jun;51(6):642-51.
[PubMed Citation] [Order full text from Infotrieve]

8) Hudepohl NS, Nasrallah HA
Antipsychotic drugs.
Handb Clin Neurol. 2012;106:657-67.
Neuroleptic medications, now referred to as antipsychotic drugs, were serendipitously discovered in the early 1950s when the phenothiazine chlorpromazine, which was used as an antihistaminic adjunct during surgery on mentally ill patients, was observed to ameliorate psychotic symptoms. Dozens of phenothiazine, and later many nonphenothiazine, antipsychotics were developed and all of them were noted to cause extrapyramidal movement disorders, which instigated the theory that schizophrenia is related to increased dopamine activity. The poor tolerability to, and nonadherence with, the first-generation antipsychotics due to akathisia, dystonia, dyskinesia, and parkinsonism led eventually to the development of the second-generation antipsychotics with more serotonin 5-HT(2) than D(2) receptor antagonism, resulting in far fewer acute and tardive movement disorders but more metabolic adverse effects, including obesity, hyperglycemia, and hyperlipidemia. Both generations have multiple effects on various organ systems, but the second-generation agents are now indicated or used not only in primary psychotic disorders and neurologically induced psychotic symptoms, but also in nonpsychotic conditions such as bipolar disorder and major depression. Future antipsychotic drugs may transcend the model of dopamine antagonism to one of glutamate modulation. [PubMed Citation] [Order full text from Infotrieve]

9) Ayalew M, Le-Niculescu H, Levey DF, Jain N, Changala B, Patel SD, Winiger E, Breier A, Shekhar A, Amdur R, Koller D, Nurnberger JI, Corvin A, Geyer M, Tsuang MT, Salomon D, Schork NJ, Fanous AH, O'Donovan MC, Niculescu AB
Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction.
Mol Psychiatry. 2012 May 15;
We have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRIN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein-coupled receptor signaling and cAMP-mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data are consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European American and one African American, increasing overlap, reproducibility and consistency of findings from single-nucleotide polymorphisms to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Finally, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology.Molecular Psychiatry advance online publication, 15 May 2012; doi:10.1038/mp.2012.37. [PubMed Citation] [Order full text from Infotrieve]

10) Leng Y, Fessler EB, Chuang DM
Neuroprotective effects of the mood stabilizer lamotrigine against glutamate excitotoxicity: roles of chromatin remodelling and Bcl-2 induction.
Int J Neuropsychopharmacol. 2012 May 8;:1-14.
Lamotrigine (LTG), a phenyltriazine derivative and anti-epileptic drug, has emerged as an effective first-line treatment for bipolar mood disorder. Like the other mood stabilizers lithium and valproate, LTG also has neuroprotective properties but its exact mechanisms remain poorly defined. The present study utilized rat cerebellar granule cells (CGCs) to examine the neuroprotective effects of LTG against glutamate-induced excitotoxicity and to investigate potential underlying mechanisms. CGCs pretreated with LTG were challenged with an excitotoxic dose of glutamate. Pretreatment caused a time- and concentration-dependent inhibition of glutamate excitotoxicity with nearly full protection at higher doses (?100 ?m), as revealed by cell viability assays and morphology. LTG treatment increased levels of acetylated histone H3 and H4 as well as dose- and time-dependently enhanced B-cell lymphoma-2 (Bcl-2) mRNA and protein levels; these changes were associated with up-regulation of the histone acetylation and activity of the Bcl-2 promoter. Importantly, lentiviral-mediated Bcl-2 silencing by shRNA reduced both LTG-induced Bcl-2 mRNA up-regulation and neuroprotection against glutamate excitotoxicity. Finally, the co-presence of a sub-effective concentration of LTG (10 ?m) with lithium or valproate produced synergistic neuroprotection. Together, our results demonstrate that the neuroprotective effects of LTG against glutamate excitotoxicity likely involve histone deacetylase inhibition and downstream up-regulation of anti-apoptotic protein Bcl-2. These underlying mechanisms may contribute to the clinical efficacy of LTG in treating bipolar disorder and warrant further investigation. [PubMed Citation] [Order full text from Infotrieve]

11) Bielau H, Brisch R, Bernard-Mittelstaedt J, Dobrowolny H, Gos T, Baumann B, Mawrin C, Bernstein HG, Bogerts B, Steiner J
Immunohistochemical evidence for impaired nitric oxide signaling of the locus coeruleus in bipolar disorder.
Brain Res. 2012 Jun 12;1459:91-9.
Nitric oxide (NO) is an important messenger in brain signaling and influences the balance of monoaminergic and glutamatergic neurotransmission. Alterations of NO signaling are thought to play a crucial role in the pathophysiology of mood disorders. The locus coeruleus (LC) comprises the largest group of norepinephrine containing neurons in the mammalian brain. These norepinephrinergic LC neurons are able to generate NO. Immunohistochemical staining of neuronal nitric oxide synthase (nNOS)-immunoreactive (ir) neurons was performed in the LC of the brains of 10 patients with bipolar I disorder (BD), 8 patients with major depressive disorder (MDD) and 16 control cases (C). Analysis of variance (ANOVA) revealed significant differences between the groups, and post hoc tests indicated a lower nNOS-ir neuron number in bipolar patients than in controls (left -34%, right -17%). The total number of Nissl-stained LC neurons showed no changes between major depressive disorder patients, bipolar patients and controls. In the mood disorder patients, illness duration correlated negatively with nNOS-ir neuronal number (r=-0.74, p=0.002). A reduced relative amount of NO in the LC of bipolar patients is likely a result of a compensation for increased glutamatergic activity. The current data on nNOS suggest a dysregulation of the nitrergic system in bipolar disorder. Future studies may clarify the potential role of glial cells in the context of the described nNOS deficit. [PubMed Citation] [Order full text from Infotrieve]

12) Daniele S, Da Pozzo E, Abelli M, Panighini A, Pini S, Gesi C, Lari L, Cardini A, Cassano GB, Martini C
Platelet uptake of GABA and glutamate in patients with bipolar disorder.
Bipolar Disord. 2012 May;14(3):301-8.
[PubMed Citation] [Order full text from Infotrieve]

13) Femen�a T, G�mez-Gal�n M, Lindskog M, Magara S
Dysfunctional hippocampal activity affects emotion and cognition in mood disorders.
Brain Res. 2012 Apr 5;
Mood disorders, such as major depressive disorder (MDD), bipolar disorder and generalized anxiety disorder usually comprise mood related as well as cognitive symptoms and the interaction between these symptoms is still not clear. Most antidepressant drugs have a positive effect on mood but do not treat the cognitive dysfunctions or even aggravate the symptoms. In this review we will evaluate the association between mood and cognition in the context of mood disorders. In the first section we will summarize the brain circuits at the intersection between cognition and emotion, highlighting the role of the hippocampus. In the second section, we will survey the contribution of the glutamate and GABA systems in the pathophysiology of mood disorders, making an effort to understand the link between emotions and cognition and how novel therapeutic approaches deal with them. In the third section we will explore the monoamine involvement in the emotion/cognition duality in the context of mood disorders. Finally we will underline the role of synaptic plasticity and neurogenesis in depression. We consider that a broader knowledge about the integrative mechanisms involved in specific aspects of mood disorders is crucial in the development of more powerful and effective antidepressant drugs. This article is part of a Special Issue entitled: Brain Integration. [PubMed Citation] [Order full text from Infotrieve]

14) Ferraro L, Antonelli T, Beggiato S, Tomasini MC, Fuxe K, Tanganelli S
The Vigilance Promoting Drug Modafinil Modulates Serotonin Transmission in the Rat Prefrontal Cortex and Dorsal Raphe Nucleus. Possible Relevance for its Postulated Antidepressant Activity.
Mini Rev Med Chem. 2012 Apr 17;
Modafinil, (RS)-2-(diphenylmethylsulfinyl)acetamide derivative (Modiodal, Provigil), is a vigilance-promoting agent which reduces sleep episodes by improving wakefulness. It is approved by the USA FDA for narcolepsy, shiftwork sleep disorder and obstructive sleep apnoea with residual excessive sleepiness despite optimal use of continuous positive airway pressure. Unlike classical psychostimulants such as amphetamine and amphetamine-like compounds, the awaking effect of modafinil is not associated with a disturbance of nighttime sleep, tolerance, and sensitization. Its precise mechanism of action is still unclear. In animal studies, modafinil and its analogues have been shown to modify dopaminergic, noradrenergic, glutamatergic, GABAergic, serotoninergic, orexinergic, and histaminergic pathways. Besides the approved use in sleep disorders, modafinil has been investigated for treatment of fatigue, impaired cognition and some symptoms in a number of other disorders. In particular, clinical studies seem to indicate that the drug could be particularly successful in the treatment of depression and its use in major depressive and bipolar disorders, has been suggested. However, the molecular mechanisms underlying this possible effect are still unknown. The present review firstly summarizes the structure-activity relationship studies and the mechanism of action of modafinil and its related compounds. Then, it focuses on data demonstrating that modafinil interacts with serotonin neuronal activity in rat frontal cortex and dorsal raphe nucleus, two brain areas linked together and involved in depression. Preclinical and clinical evidence of a positive interaction between modafinil and classical antidepressant drugs, is also summarized. [PubMed Citation] [Order full text from Infotrieve]

15) Tao R, Li C, Newburn EN, Ye T, Lipska BK, Herman MM, Weinberger DR, Kleinman JE, Hyde TM
Transcript-specific associations of SLC12A5 (KCC2) in human prefrontal cortex with development, schizophrenia, and affective disorders.
J Neurosci. 2012 Apr 11;32(15):5216-22.
The neuron-specific K(+)-Cl(-) cotransporter SLC12A5, also known as KCC2, helps mediate the electrophysiological effects of GABA. The pattern of KCC2 expression during early brain development suggests that its upregulation drives the postsynaptic switch of GABA from excitation to inhibition. We previously found decreased expression of full-length KCC2 in the postmortem hippocampus of patients with schizophrenia, but not in the dorsolateral prefrontal cortex (DLPFC). Using PCR and rapid amplification of cDNA ends, we discovered several previously unrecognized alternative KCC2 transcripts in both human adult and fetal brain in addition to the previously identified full-length (NM_020708.3) and truncated (AK098371) transcripts. We measured the expression levels of four relatively abundant truncated splice variants, including three novel transcripts (?EXON6, EXON2B, and EXON6B) and one previously described transcript (AK098371), in a large human cohort of nonpsychiatric controls across the lifespan, and in patients with schizophrenia and affective disorders. In SH-SY5Y cell lines, these transcripts were translated into proteins and expressed at their predicted sizes. Expression of the EXON6B transcript is increased in the DLPFC of patients with schizophrenia (p = 0.03) but decreased in patients with major depression (p = 0.04). The expression of AK098371 is associated with a GAD1 single nucleotide polymorphism (rs3749034) that previously has been associated with GAD67 expression and risk for schizophrenia. Our data confirm the developmental regulation of KCC2 expression, and provide evidence that KCC2 transcripts are differentially expressed in schizophrenia and affective disorders. Alternate transcripts from KCC2 may participate in the abnormal GABA signaling in the DLPFC associated with schizophrenia. [PubMed Citation] [Order full text from Infotrieve]

16) Dean OM, Data-Franco J, Giorlando F, Berk M
Minocycline: therapeutic potential in psychiatry.
CNS Drugs. 2012 May 1;26(5):391-401.
Pharmacological interventions to treat psychiatric illness have previously focused on modifying dysfunctional neurotransmitter systems to improve symptoms. However, imperfect understanding of the aetiology of these heterogeneous syndromes has been associated with poor treatment outcomes for many individuals. Growing evidence suggests that oxidative stress, inflammation, changes in glutamatergic pathways and neurotrophins play important roles in many psychiatric illnesses including mood disorders, schizophrenia and addiction. These novel insights into pathophysiology allow new treatment targets to be explored. Minocycline is an antibiotic that can modulate glutamate-induced excitotoxicity, and has antioxidant, anti-inflammatory and neuroprotective effects. Given that these mechanisms overlap with the newly understood pathophysiological pathways, minocycline has potential as an adjunctive treatment in psychiatry. To date there have been promising clinical indications that minocycline may be a useful treatment in psychiatry, albeit from small trials most of which were not placebo controlled. Case reports of individuals with schizophrenia, psychotic symptoms and bipolar depression have shown serendipitous benefits of minocycline treatment on psychiatric symptoms. Minocycline has been trialled in open-label or small randomized controlled trials in psychiatry. Results vary, with findings supporting use in schizophrenia, but showing less benefit for nicotine dependence and obsessive-compulsive disorder. Given the limited data from rigorous clinical trials, further research is required. However, taken together, the current evidence suggests minocycline may be a promising novel therapy in psychiatry. [PubMed Citation] [Order full text from Infotrieve]

17) Lyddon R, Navarrett S, Dracheva S
Ionotropic glutamate receptor mRNA editing in the prefrontal cortex: no alterations in schizophrenia or bipolar disorder.
J Psychiatry Neurosci. 2012 Jul;37(4):267-72.
Background: Dysfunction of glutamate neurotransmission has been implicated in the pathology of schizophrenia and bipolar disorder, and one mechanism by which glutamate signalling can be altered is through RNA editing of ionotropic glutamate receptors (iGluRs). The objectives of the present study were to evaluate the editing status of iGluRs in the human prefrontal cortex, determine whether iGluR editing is associated with psychiatric disease or suicide and evaluate a potential association between editing and alternative splicing in the ?-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) iGluR subunits' pre-mRNA. Methods: We studied specimens derived from patients with antemortem diagnoses of bipolar disorder (n = 31) or schizophrenia (n = 34) who died by suicide or other causes, and from psychiatrically healthy controls (n = 34) who died from causes other than suicide. The RNA editing at all 8 editing sites within AMPA (GluA2-4 subunits) and kainate (GluK1-2 subunits) iGluRs was analyzed using a novel real-time quantitative polymerase chain reaction assay. Results: No differences in editing were detected among schizophrenia, bipolar or control groups or between suicide completers and patients who died from causes other than suicide. The editing efficiency was significantly higher in the flop than in the flip splicoforms of GluA3-4 AMPA subunits (all p < 0.001). Limitations: The study is limited by the near absence of specimens from medicationnaive psychiatric patients and considerable variation in medication regimens among individuals, both of which introduce considerable uncertainty into the analysis of potential medication effects. Conclusion: We found that iGluR RNA editing status was not associated with bipolar disorder, schizophrenia or suicide. Differences in editing between flip and flop splicoforms suggest that glutamate sensitivity of receptors containing GluA3 and/or GluA4 flop subunits is moderated as a result of increased editing. [PubMed Citation] [Order full text from Infotrieve]

18) Ayoub MA, Angelicheva D, Vile D, Chandler D, Morar B, Cavanaugh JA, Visscher PM, Jablensky A, Pfleger KD, Kalaydjieva L
Deleterious GRM1 mutations in schizophrenia.
PLoS One. 2012;7(3):e32849.
We analysed a phenotypically well-characterised sample of 450 schziophrenia patients and 605 controls for rare non-synonymous single nucleotide polymorphisms (nsSNPs) in the GRM1 gene, their functional effects and family segregation. GRM1 encodes the metabotropic glutamate receptor 1 (mGluR1), whose documented role as a modulator of neuronal signalling and synaptic plasticity makes it a plausible schizophrenia candidate. In a recent study, this gene was shown to harbour a cluster of deleterious nsSNPs within a functionally important domain of the receptor, in patients with schizophrenia and bipolar disorder. Our Sanger sequencing of the GRM1 coding regions detected equal numbers of nsSNPs in cases and controls, however the two groups differed in terms of the potential effects of the variants on receptor function: 6/6 case-specific and only 1/6 control-specific nsSNPs were predicted to be deleterious. Our in-vitro experimental follow-up of the case-specific mutants showed that 4/6 led to significantly reduced inositol phosphate production, indicating impaired function of the major mGluR1 signalling pathway; 1/6 had reduced cell membrane expression; inconclusive results were obtained in 1/6. Family segregation analysis indicated that these deleterious nsSNPs were inherited. Interestingly, four of the families were affected by multiple neuropsychiatric conditions, not limited to schizophrenia, and the mutations were detected in relatives with schizophrenia, depression and anxiety, drug and alcohol dependence, and epilepsy. Our findings suggest a possible mGluR1 contribution to diverse psychiatric conditions, supporting the modulatory role of the receptor in such conditions as proposed previously on the basis of in vitro experiments and animal studies. [PubMed Citation] [Order full text from Infotrieve]

19) Pauli A, Prata DP, Mechelli A, Picchioni M, Fu CH, Chaddock CA, Kane F, Kalidindi S, McDonald C, Kravariti E, Toulopoulou T, Bramon E, Walshe M, Ehlert N, Georgiades A, Murray R, Collier DA, McGuire P
Interaction between effects of genes coding for dopamine and glutamate transmission on striatal and parahippocampal function.
Hum Brain Mapp. 2012 Mar 22;
The genes for the dopamine transporter (DAT) and the D-Amino acid oxidase activator (DAOA or G72) have been independently implicated in the risk for schizophrenia and in bipolar disorder and/or their related intermediate phenotypes. DAT and G72 respectively modulate central dopamine and glutamate transmission, the two systems most robustly implicated in these disorders. Contemporary studies have demonstrated that elevated dopamine function is associated with glutamatergic dysfunction in psychotic disorders. Using functional magnetic resonance imaging we examined whether there was an interaction between the effects of genes that influence dopamine and glutamate transmission (DAT and G72) on regional brain activation during verbal fluency, which is known to be abnormal in psychosis, in 80 healthy volunteers. Significant interactions between the effects of G72 and DAT polymorphisms on activation were evident in the striatum, parahippocampal gyrus, and supramarginal/angular gyri bilaterally, the right insula, in the right pre-/postcentral and the left posterior cingulate/retrosplenial gyri (P < 0.05, FDR-corrected across the whole brain). This provides evidence that interactions between the dopamine and the glutamate system, thought to be altered in psychosis, have an impact in executive processing which can be modulated by common genetic variation. Hum Brain Mapp, 2012. � 2012 Wiley Periodicals, Inc. [PubMed Citation] [Order full text from Infotrieve]

20) Yadav R, Gupta SC, Hillman BG, Bhatt JM, Stairs DJ, Dravid SM
Deletion of glutamate delta-1 receptor in mouse leads to aberrant emotional and social behaviors.
PLoS One. 2012;7(3):e32969.
The delta family of ionotropic glutamate receptors consists of glutamate ?1 (GluD1) and glutamate ?2 (GluD2) receptors. While the role of GluD2 in the regulation of cerebellar physiology is well understood, the function of GluD1 in the central nervous system remains elusive. We demonstrate for the first time that deletion of GluD1 leads to abnormal emotional and social behaviors. We found that GluD1 knockout mice (GluD1 KO) were hyperactive, manifested lower anxiety-like behavior, depression-like behavior in a forced swim test and robust aggression in the resident-intruder test. Chronic lithium rescued the depression-like behavior in GluD1 KO. GluD1 KO mice also manifested deficits in social interaction. In the sociability test, GluD1 KO mice spent more time interacting with an inanimate object compared to a conspecific mouse. D-Cycloserine (DCS) administration was able to rescue social interaction deficits observed in GluD1 KO mice. At a molecular level synaptoneurosome preparations revealed lower GluA1 and GluA2 subunit expression in the prefrontal cortex and higher GluA1, GluK2 and PSD95 expression in the amygdala of GluD1 KO. Moreover, DCS normalized the lower GluA1 expression in prefrontal cortex of GluD1 KO. We propose that deletion of GluD1 leads to aberrant circuitry in prefrontal cortex and amygdala owing to its potential role in presynaptic differentiation and synapse formation. Furthermore, these findings are in agreement with the human genetic studies suggesting a strong association of GRID1 gene with several neuropsychiatric disorders including schizophrenia, bipolar disorder, autism spectrum disorders and major depressive disorder. [PubMed Citation] [Order full text from Infotrieve]