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.
(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.
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]
Mauricio, Kwock, Lester, Courvoisie, Helen, Hooper, Stephen R.
MR Spectroscopy in Children with Bipolar Affective Disorder: Preliminary Observations
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
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.
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]
RE, Meador-Woodruff JH.
Striatal excitatory amino acid transporter
transcript expression in schizophrenia, bipolar disorder, and major depressive
Neuropsychopharmacology. 2002 Mar;26(3):368-75.
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
Mundo E, Tharmalingham S, Neves-Pereira M, Dalton
EJ, Macciardi F, Parikh SV, Bolonna A, Kerwin RW, Arranz MJ, Makoff AJ, Kennedy
Evidence that the N-methyl-D-aspartate subunit 1 receptor gene
(GRIN1) confers susceptibility to bipolar disorder.
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]
AJ, Deakin JF.
Asymmetrical reductions of hippocampal NMDAR1 glutamate
receptor mRNA in the psychoses.
Neuroreport. 2001 Sep 17;12(13):2971-4.
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.
hippocampal NMDA, but not kainate or AMPA receptors in bipolar disorder.
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]
SM, Meador-Woodruff JH.
Abnormalities of the NMDA Receptor and Associated
Intracellular Molecules in the Thalamus in Schizophrenia and Bipolar Disorder.
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]
Glutamate receptor genes: susceptibility factors in schizophrenia
and depressive disorders?
Mol Neurobiol. 2002 Apr;25(2):191-212.
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."
Meador-Woodruff JH, Hogg AJ Jr, Smith RE.
ionotropic glutamate receptor expression in schizophrenia, bipolar disorder, and
major depressive disorder.
Brain Res Bull. 2001 Jul 15;55(5):631-40.
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.
subunit immunoreactivity on apical pyramidal cell dendrites in hippocampus of
schizophrenics and manic depressives.
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.
the link between the GABA-deficit hypothesis and the dopaminergic- and glutamatergic
theories of psychosis.
J Neural Transm. 2003 Jul;110(7):803-12.
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]
J, Gray NA, Falke CA, Chen W, Yuan P, Szabo ST, Einat H, Manji HK.
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.
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.
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.
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]
S, Stone D, Walsh J, Shick J, Koul P, Benes FM.
expression of glutamic acid decarboxylase 65 and 67 messenger RNA in bipolar disorder
Arch Gen Psychiatry. 2002 Jun;59(6):521-9.
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]
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.
in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia
and bipolar disorder: a postmortem brain study.
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]
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.
Natl Acad Sci U S A. 2002 Dec 24;99(26):17095-100. Epub 2002 Dec 12.
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
Ketter TA, Wang PW.
differential roles of GABAergic and antiglutamatergic agents in bipolar disorders.
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, 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.
prevents ketamine but not amphetamine-induced deficits in prepulse inhibition
Psychopharmacology (Berl). 2003 Apr 16 [Epub ahead
"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]
F. Dixon, and Lowell E. Hokin
Lithium acutely inhibits and chronically
up-regulates and stabilizes glutamate uptake by presynaptic nerve endings in mouse
PNAS 95: 8363-8368, 1998.
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
Bown CD, Wang JF, Young LT.
of N-methyl-D-aspartate-mediated cytoplasmic vacuolization in primary rat hippocampal
neurons by mood stabilizers.
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]
GE, Young LT, Reagan LP, Chen B, McEwen BS.
remodeling in hippocampus: prevention by lithium treatment.
Natl Acad Sci U S A. 2004 Mar 16;101(11):3973-8. Epub 2004 Mar 04.
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]