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]