Biomedical subjects

Brian Dean

Publications and source records attributed to Brian Dean.

At least 19 recordsLinked to original sources

PubMed2006

Decreased NR1, NR2A, and SAP102 transcript expression in the hippocampus in bipolar disorder.

OBJECTIVES: Schizophrenia is associated with dysfunction of glutamatergic neurotransmission, and several studies have suggested glutamatergic abnormalities in bipolar disorder. Recent data suggest involvement of the NMDA receptor signaling complex, which includes NMDA receptor subunits as well as associated intracellular interacting proteins critical for NMDA receptor assembly, trafficking, and activation; the most well-characterized being PSD93, PSD95, SAP102, and NF-L. Previously, studies from our laboratories have described changes in glutamate receptor subunit transcript and binding site expression in schizophrenia and changes in NMDA receptor binding site expression in bipolar disorder in postmortem brain tissue. In the present work, we focus on the expression of these molecules in hippocampus in schizophrenia and bipolar affective disorder I. METHODS: We performed in situ hybridization to assess hippocampal expression of the transcripts encoding NMDA receptor subunits NR1, 2A, 2B, 2C and 2D, and the transcripts for the NMDA receptor associated PSD proteins PSD95, PSD93, NF-L, and SAP102 in subjects with schizophrenia, bipolar affective disorder I, and a comparison group. We also measured [(3)H]CGP39653 and [(3)H]MK-801 binding site expression in the hippocampus in schizophrenia. RESULTS: There was a significant decrease in the expression of transcripts for NR1 and NR2A subunits and SAP102 in bipolar disorder. We did not detect any changes in these transcripts or in binding site expression in the hippocampus in schizophrenia. CONCLUSIONS: We propose that the NMDA receptor signaling complex, including the intracellular machinery that is coupled to the NMDA receptor subunits, is abnormal in the hippocampus in bipolar disorder. These data suggest that bipolar disorder might be associated with abnormalities of glutamate-linked intracellular signaling and trafficking processes.

Binding Sites↗

PubMed2006

Cortical serotonin7, 1D and 1F receptors: effects of schizophrenia, suicide and antipsychotic drug treatment.

Abnormalities in serotonergic function are thought to be important in the pathology of schizophrenia. Postmortem CNS studies suggest that levels of serotonin receptors may be altered in the cortex of subjects with schizophrenia. Seeking to expand this hypothesis we have examined the effect of schizophrenia and antipsychotic drug treatments on the levels of cortical serotonin7, 1D and 1F receptors. There was a significant decrease in the binding of [3H]SB 269970 to the serotonin7 receptor in Brodmann's area 9 from subjects with schizophrenia compared to controls (Mean+/-S.E.M.: 8.3+/-0.76 vs. 11.0+/-0.64 fmol/mg ETE; p<0.05) and an increase in the binding of that radioligand in the cortex of rats treated with haloperidol (p=0.03). There were no significant differences in [3H]sumatriptan binding to the serotonin1D or serotonin1F receptor in Brodmann's area 9 from subjects with schizophrenia. There was a significant increase in [3H]sumatriptan binding to the serotonin1D in binding Layer 2 from subjects who had potentially died by suicide that was not present in other binding layers or for the serotonin1F or serotonin7 receptors. There was decrease in [3H]sumatriptan binding to the serotonin1D, but not serotonin1F, receptors across all cortical binding layers in rats treated with haloperidol. These data would be consistent with the hypothesis that decreased levels of serotonin7 receptors in Brodmann's area 9 may be involved in the pathological processes of schizophrenia and that levels of cortical serotonin7 and 1D receptors can be affected by antipsychotic drug treatment.

Adult↗

PubMed2006

Clozapine bioactivation induces dose-dependent, drug-specific toxicity of human bone marrow stromal cells: a potential in vitro system for the study of agranulocytosis.

Clozapine, an atypical antipsychotic drug effective in treatment of refractory schizophrenia causes potentially life-threatening agranulocytosis. The drug undergoes bioactivation to a toxic, chemically reactive intermediate with capacity to target stromal cells, central components of the bone marrow microenvironment implicated in neutrophil development. To identify possible mechanisms underpinning disruption of stroma as a site of drug bioactivation, toxicity was induced in vitro. Therefore metabolite generation procedures utilizing HOCl or HRP-H(2)O(2) as primary components involved in clozapine metabolism were adapted for stromal culture and coupled with viability determinations. Drug oxidation by HOCl was less toxic to stromal cells than HRP-H(2)O(2) based methods. More specifically, clozapine bioactivation by HRP-H(2)O(2) caused dose-dependent inhibition of stromal viability at therapeutically relevant concentrations. Differences in susceptibility of HAS303 and LP101 cells to the clozapine nitrenium ion were also evident. Stromal cell death was attributed to clozapine in the presence of a complete metabolising system comprising HRP and H(2)O(2). In the absence of a complete metabolising system clozapine was not cytotoxic. For LP101 cells, drug plus HRP (minus H(2)O(2)) also induced toxicity. Importantly, other antipsychotic drugs including risperidone, olanzapine and haloperidol when bioactivated, were not cytotoxic, indicating system specificity for clozapine. Exogenous GSH, N-acetylcysteine, l-ascorbic acid, catalase, and sodium azide afforded protection to cells whereas S-methylGSH, GSSG, ketoprofen and proadifen did not. Thus functional data derived from the in vitro stromal system defined in these studies may enable further investigation of the mechanisms subserving stromal impairment in clozapine-induced agranulocytosis and direct attention to improved methods for its prevention.

Agranulocytosis↗

PubMed2006

Serotonin 1a receptor and associated G-protein activation in schizophrenia and bipolar disorder.

Abnormalities in the serotonergic signalling system, including the serotonin 1a receptor, have been implicated in the pathogenesis of schizophrenia and bipolar 1 disorder. However, there is no consensus on whether the density of the serotonin 1a receptor and/or the activity of the G-proteins linking the receptor to the intracellular cascade are altered in these disease states. To address these issues, tissue obtained postmortem from four cortical regions was used to measure [3H] 8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT) binding and 8-OH-DPAT-stimulated guanosine 5'-[gamma-thio]triphosphate (GTPgammaS) binding to determine if either parameter is altered in schizophrenia or bipolar I disorder. There was an effect of diagnosis on the level of [3H] 8-OH-DPAT binding that may indicate a global change in the density of serotonin 1a receptors, although this effect did not reach significance in any individual brain region. The activation of serotonin 1a receptors did not differ significantly with diagnoses. However, in the outer cortical layers, there appeared to be a dissociation between the number of receptors available and the extent of ligand-induced GTPgammaS binding, suggesting considerable receptor reserve. In addition, comparing gender independent of diagnoses, a decrease in the levels of serotonin 1a receptors was observed in the cortex of female subjects. These data indicates that there may be subtle changes in serotonin 1a receptors across the cortex in schizophrenia or bipolar I disorder and suggests a gender discordance in receptor levels.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2006

Genome-wide expression analysis detects eight genes with robust alterations specific to bipolar I disorder: relevance to neuronal network perturbation.

The limited number of genome-wide transcriptome analyses using the postmortem brains of bipolar disorder sufferers has not produced a clear consensus on the molecular pathways affected by the disorder. To expand the knowledge in this area, we examined the expression levels of more than 12 000 genes in Brodmann's Area (BA), 46 (dorsolateral prefrontal cortex) from bipolar I disorder and control samples using Affymetrix GeneChips. This analysis detected 108 differentially expressed genes in bipolar brains. Validation studies using quantitative RT-PCR on the two original diagnostic cohorts plus tissue from schizophrenic subjects, confirmed the differential expressions of eight genes (RAP1GA1, SST, HLA-DRA, KATNB1, PURA, NDUFV2, STAR and PAFAH1B3) in a bipolar-specific manner and one gene (CCL3) which was downregulated in both bipolar and schizophrenic brains. Of these, protein levels of RAP1GA1 (RAP1 GTPase activating protein 1) showed a trend of increase in BA46 from bipolar brains, in keeping with mRNA transcript levels. Transmission disequilibrium analysis of the nine genes using 43 single nucleotide polymorphisms (SNPs) in 229 National Institute of Mental Health bipolar trios exposed nominal SNP association and modest empirical haplotypic association (P=0.033) between SST (somatostatin) and disease. Finally, gene network analysis using the currently obtained expression data highlighted cellular growth and nervous system development pathways as potential targets in the molecular pathophysiology of bipolar disorder.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed2006

Postmortem brain calcineurin protein levels in schizophrenia patients are not different from controls.

Calcineurin (CaN), also designated as protein phosphatase 2B, is a major Ca2+/calmodulin-binding protein in the brain and the only serine/threonine phosphatase under the control of Ca2+/calmodulin. CaN activity has been implicated in downstream regulation of dopaminergic signal transduction and in NMDA receptor-dependent synaptic plasticity. Thus, it serves as a point of convergence for the abnormalities of these two neurotransmitter systems in schizophrenia. The aim of the present study was to determine if levels of CaN were altered in two schizophrenia- and CaN-related brain regions--the dorsolateral prefrontal cortex and hippocampus from subjects with schizophrenia compared to that in tissue from age and sex matched controls. CaN protein levels were measured by Western-blot analysis in samples from 15 schizophrenia patients vs. 15 control subjects. No significant differences in CaN protein levels were found either in the prefrontal cortex or in the hippocampus of schizophrenia patients compared to matched control subjects. Our result of lack of difference does not support the concept that brain CaN levels are a pathophysiological factor in this disorder. Further studies with antibodies against specific CaN catalytic subunit isoforms (presently unavailable) are required to resolve this issue.

Adult↗

PubMed2006

Regionally specific changes in levels of cortical S100beta in bipolar 1 disorder but not schizophrenia.

OBJECTIVE: To determine if levels of the glial-derived proteins S100beta and glial acidic fibrillary protein (GFAP) and the pro- and antiapoptotic proteins p53 and Bcl-2 were altered in the cortex of subjects with schizophrenia or bipolar 1 disorder. METHOD: Levels of S100beta, GFAP, p53 and Bcl-2 were measured in cortex (Brodmann's Areas (BAs) 9, 10, 46 and 40) of control subjects and subjects with schizophrenia, bipolar 1 disorder and in the cortex of rats treated with haloperidol or lithium using protein-specific antibodies and western blot analysis. RESULTS: Levels of S100beta were decreased in BA 9 and increased in BA 40 from subjects with bipolar 1 disorder. Levels of this protein were not altered in other CNS regions, in schizophrenia or in the cortex of rats treated with haloperidol or lithium. No changes in levels of the other three proteins were detected across diagnoses. CONCLUSIONS: Regionally selective changes in cortical S100beta may be associated with the pathology of bipolar 1 disorder and may reflect derangements in neuronal death or survival.

Adult↗

PubMed2005

No change in cortical muscarinic M2, M3 receptors or [35S]GTPgammaS binding in schizophrenia.

Muscarinic M1, but not M4, receptors have been shown to be decreased in Brodmann's area (BA) 9 obtained postmortem from subjects with schizophrenia. This study extends that data by measuring levels of muscarinic M2 and M3 receptor protein and mRNAs in BA 9 and BA 40 from the same cohorts of subjects used in the study of M1 and M4 receptors. In addition, the ability of carbachol to stimulate muscarinic receptors that signal through the Gi/o G-proteins was measured in BA 9 from the same cohorts of subjects. There were no changes in levels of muscarinic M2 or M3 protein or M3 mRNA with diagnosis in either CNS region. M2 receptor mRNA could not be detected in BA 9 or BA 40. Finally, carbachol-stimulated GTPgammaS binding did not differ between the diagnostic cohorts in BA 9 (p = 0.64). These data add considerable weight to the argument that the muscarinic M1 receptor is the muscarinic receptor predominantly affected in BA 9 by the pathology of schizophrenia. Given the widespread changes in muscarinic receptors identified in the CNS of subjects of schizophrenia using functional neuroimaging it remains possible that receptors other than the M1 receptor may be altered in different CNS regions.

Adult↗

PubMed2005

N-Ethylmaleimide sensitive factor in the cortex of subjects with schizophrenia and bipolar I disorder.

N-Ethylmaleimide sensitive factor (NSF) is a presynaptic protein that has been suggested to be differentially expressed in the cortex of schizophrenic subjects through both high-throughput proteomic and genomic screening studies. Thus, to expand upon these studies we measured NSF using Western blotting in four regions of the cortex (BA9, 10, 40 and 46), in a cohort comprising 20 schizophrenic subjects, 8 bipolar I disorder subjects, and 20 control subjects. There was no significant difference in NSF levels between diagnostic cohorts in any of the four cortical regions. These findings highlight the importance of validating findings from high-throughput screening studies and do not support changes in cortical NSF as being of significance in schizophrenia or bipolar 1 disorder.

Adult↗

PubMed2005

Changes in hippocampal GABAA receptor subunit composition in bipolar 1 disorder.

Postmortem CNS studies have suggested an uncoupling of the gamma-aminobutyric acid (GABA) and benzodiazepine binding sites on the hippocampal GABA(A) receptor in schizophrenia. The GABA(A) receptor is an assembly of discrete subunits that form a ligand-gated ion channel, the binding characteristics of which are defined by receptor subunit composition. Thus, a likely explanation for an uncoupling between the GABA and benzodiazepine binding sites on the GABA(A) receptor would be a change in receptor subunit composition. To test this hypothesis we measured the density of GABA ([(3)H]muscimol) and benzodiazepine ([(3)H]flumazenil) binding sites on the GABA(A) receptor in hippocampi, obtained postmortem, from schizophrenic, bipolar I disorder and control subjects. In addition, we measured the amount of [(3)H]flumazenil binding that could be displaced with zolpidem and clonazepam. Levels of both [(3)H]muscimol and [(3)H]flumazenil binding were significantly decreased in part of the CA2 from subjects with schizophrenia; the decrease in [(3)H]flumazenil being due to decreases in both zolpidem-sensitive and -insensitive radioligand binding. There were complex regionally specific changes in [(3)H]muscimol binding in the hippocampus from subjects with bipolar I disorder but there were no significant changes in the overall levels of [(3)H]flumazenil binding. There were significant decreases in zolpidem-sensitive and increases in zolpidem-insensitive [(3)H]flumazenil binding in most regions of the sections of the hippocampal formation studied in bipolar I disorder. Unlike [(3)H]flumazenil, zolpidem does not bind to the alpha5 subunit of the GABA(A) receptor; therefore, we postulate that there is an increase in GABA(A) receptors containing alpha5 subunit in the hippocampus from subjects with bipolar I disorder.

Adult↗

PubMed2005

Clozapine decreases [3H] CP 55940 binding to the cannabinoid 1 receptor in the rat nucleus accumbens.

Antipsychotic drugs are effective in the treatment of cannabis-induced psychosis, but only clozapine appears effective in the treatment of comorbid schizophrenia and cannabis use. The unique effects of clozapine on cannabis use could, therefore, be due to an as yet unidentified interaction between clozapine and the endogenous cannabinoid system. To address this hypothesis, we used in situ radioligand binding and quantitative autoradiography with the selective cannabinoid CB1 receptor agonist, (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (side chain-2,3,4(N)-3H) ([3H]CP 55940) to measure the density of the CB1 receptor in frontal cortex, hippocampus, nucleus accumbens and striatum from rats treated with a variety of antipsychotic drugs. Clozapine significantly decreased [3H]CP 55940 binding in the nucleus accumbens compared with vehicle after 1 (35.0+/-14.0 vs. 71.2+/-8.5 fmol/mg estimated tissue equivalent (ete); P = 0.03) and 3 months (42.3+/-4.0 vs. 71.1+/-16.3 fmol/mg ete; P < 0.04) of treatment, an effect not observed with haloperidol, chlorpromazine or olanzapine. In rats treated with clozapine for 3 months and then left for 1 month without treatment, [3H]CP 55940 binding was not different in the nucleus accumbens (100.5+/-22.2 vs. 100.9+/-25.4 fmol/mg ete; P > 0.10). By contrast, there were significant increases in accumbal [3H]CP 55940 binding in rats treated with haloperidol (136.5+/-14.2 fmol/mg ete; P < 0.05), chlorpromazine (137.4+/-12.7 fmol/mg ete; P < 0.05) and olanzapine (144.7+/-10.1 fmol/mg ete; P < 0.01). These data indicate that in the nucleus accumbens clozapine differs from other antipsychotic drugs in its effects on [3H]CP 55940 binding. If these results can be extrapolated into humans, then this effect of clozapine on the CB1 receptor may be a mechanism that makes it uniquely effective in schizophrenia and comorbid cannabis use.

Analgesics↗

PubMed2005

Brain distribution of selected antipsychotics in schizophrenia.

The brain distribution of phenothiazine antipsychotics in 22 confirmed schizophrenic and 11 control subjects were collected at autopsy. Specimens were homogenized, extracted with n-butyl chloride, and analyzed via liquid chromatography-mass spectrometry, using atmospheric pressure electrospray ionization operating in the positive mode. Drug concentrations normalized for those observed in cerebellum showed three distinct patterns of distribution corresponding to different structural features of each type of phenothiazine. Those drugs with high affinity for dopamine receptors were detected in the highest concentrations in regions with high concentrations of such receptors. However, those associated with relatively lower dopaminergic activity were found in the highest concentration in the occipital cortex, a region with a relatively low concentration of dopamine receptors. The regional brain distribution of thioridazine and its metabolites was concentration dependent. These results have implications for determining the role of these drugs in the sudden and unexpected deaths of schizophrenics.

Adult↗

PubMed2005

Differential changes in apolipoprotein E in schizophrenia and bipolar I disorder.

BACKGROUND: This study extends an initial finding of increased levels of apoE in Brodmann's area (BA) 9 from subjects with schizophrenia to determine if apoE is altered in other brain regions and in brains from subjects with bipolar I disorder (BID). METHODS: ApoE was quantified apoE in BA 9, 10, 40, 46 and caudate putamen from control (n = 18), schizophrenic (n = 19) and BID (n = 8) subjects using Western blotting. RESULTS: In schizophrenia, there was increased apoE in BA9 (mean +/- SEM: schizophrenia 3.8 +/- .18 vs. control 3.2 +/- .19) and BA46 (schizophrenia 2.7 +/- .26 vs. control 1.6 +/- .20). In BID, increased levels of the apolipoprotein were detected in the caudate putamen (BID 3.3 +/- .44 vs. control 2.4 +/- .19) and BA9 (BID 4.0 +/- .27 vs. control 3.2 +/- .19) with a decrease in apoE being measured in BA10 (BID 1.6 +/- .16 vs. control 3.9 +/- .53). CONCLUSIONS: This study has shown disease specific, regionally discrete changes in levels of apoE in brain obtained post mortem from schizophrenic and BID subjects. Our data adds weight to the hypothesis that changes in the levels of apolipoproteins may be involved in the pathologies of schizophrenia and bipolar disorder.

Adult↗

PubMed2005

A family-based association study and gene expression analyses of netrin-G1 and -G2 genes in schizophrenia.

BACKGROUND: The netrin-G1 (NTNG1) and -G2 (NTNG2) genes, recently cloned from mouse, play a role in the formation and/or maintenance of glutamatergic neural circuitry. Accumulating evidence strongly suggests that disturbances of neuronal development and the N-methyl-d-aspartate receptor-mediated signaling system might represent a potential pathophysiology in schizophrenia. We therefore set out to examine the genetic contribution of human NTNG1 and NTNG2 to schizophrenia. METHODS: Twenty-one single nucleotide polymorphisms (SNPs) from NTNG1 and 10 SNPs from NTNG2 were analyzed in 124 schizophrenic pedigrees. All genotypes were determined with the TaqMan assay. The expression levels of NTNG1 and NTNG2 were examined in the frontal (Brodmann's Area [BA]11 and BA46) and temporal (BA22) cortices from schizophrenic and control postmortem brains. The isoform-specific expression of NTNG1 splice variants was assessed in these samples. RESULTS: Specific haplotypes encompassing alternatively spliced exons of NTNG1 were associated with schizophrenia, and concordantly, messenger ribonucleic acid isoform expression was significantly different between schizophrenic and control brains. An association between NTNG2 and schizophrenia was also observed with SNPs and haplotypes that clustered in the 5' region of the gene. CONCLUSIONS: The NTNG1 and NTNG2 genes might be relevant to the pathophysiology of schizophrenia.

Adult↗

PubMed2005

5-HT2A and muscarinic receptors in schizophrenia: a postmortem study.

Although evidence suggests that 5-HT(2A) and muscarinic M1/M4 receptors are implicated in the pathology of schizophrenia, the results are not conclusive. In the present study we tested the hypothesis that binding of 5-HT(2A) and M1/M4 receptors is altered in the postmortem brain of schizophrenia subjects. Quantitative autoradiography was employed to measure [(3)H]ketanserin binding to 5-HT(2A) receptors and [(3)H]pirenzepine binding to both M1 and M4 receptors in Brodmann's area 9 (BA9), caudate/putamen, and the hippocampal formation from six schizophrenic and six control subjects. A significant reduction in the density of 5HT(2A) receptors in BA 9 of schizophrenic subjects was observed (p=0.036). No significant difference was observed in the density of 5HT(2A) receptors in the hippocampus or caudate/putamen between the two groups. No significant changes in the density of M1/M4 receptors was observed in these three regions between the two groups. These findings support a possible involvement of the serotonergic system in the pathology of schizophrenia.

Aged↗

PubMed2005

Cortical glutamatergic markers in schizophrenia.

Post-mortem studies have yet to produce consistent findings on cortical glutamatergic markers in schizophrenia; therefore, it is not possible to fully understand the role of abnormal glutamatergic function in the pathology of the disorder. To better understand the changes in cortical glutamatergic markers in schizophrenia, we measured the binding of radioligands to the ionotropic glutamate receptors (N-methyl D-aspartate, [3H]CGP39653, [3H]MK-801), amino-3-hydroxy-5-methyl-4-isoxazole ([3H]AMPA), kainate ([3H]kainate), and the high-affinity glutamate uptake site ([3H]aspartate) using in situ radioligand binding with autoradiography and levels of mRNA for kainate receptors using in situ hybridization in the dorsolateral prefrontal cortex from 20 subjects with schizophrenia and 20 controls matched for age and sex. Levels of [3H]kainate binding were significantly decreased in cortical laminae I-II (p = 0.01), III-IV (p < 0.05), and V-VI (p < 0.01) from subjects with schizophrenia. By contrast, levels of [3H]MK-801, [3H]AMPA, [3H]aspartate, or [3H]CGP39653 binding did not differ between the diagnostic cohorts. Levels of mRNA for the GluR5 subunit were decreased overall (p < 0.05), with no changes in levels of mRNA for GluR6, GluR7, KA1, or KA2 in tissue from subjects with schizophrenia. These data indicate that the decreased number of kainate receptors in the dorsolateral prefrontal cortex in schizophrenia may result, in part, from reduced expression of the GluR5 receptor subunits.

2-Amino-5-phosphonovalerate↗

PubMed2004

Hippocampal 5-hydroxytryptamine receptors: abnormalities in postmortem brain from schizophrenic subjects.

There is strong evidence that hippocampal 5-hydroxytryptamine (5-HT) systems are affected in schizophrenia and hence we have studied a number of markers of the 5-HT system in hippocampi from subjects with schizophrenia. Using in situ radioligand binding with autoradiography we measured [(3)H]proplyamino-8-hydroxy-1,2,3,4-tetrahydronapthalene, [(3)H]ketanserin and [(3)H]sumatriptan binding in hippocampi from 20 schizophrenic and 20 control subjects. There were significant decreases in the density of [(3)H]ketanserin binding to the 5-HT(2A) receptor (5-HT(2A)R) in the Cornu Ammonis (CA) 3 (p=0.006), CA 1 (stratum radiatum p=0.02; pyramidal layer p=0.0008) and subiculum (pyramidal layer p=0.0004), as well as methiothepin-insensitive [(3)H]sumatriptan binding to the 5-HT(1F)R in the CA 1 (p=0.016), stratum radiatum/lacunosum moleculare (p=0.04) and subiculum (p=0.015) from subjects with schizophrenia. There were no differences in the densities of 5-HT(1A)R, 5-HT(1D)R or 5-HT(4)R in hippocampi from subjects with schizophrenia. These data support the hypothesis that regionally specific reductions in the density of the 5-HT(2A)R and 5-HT(1F)R are a component of the pathological processes underlying schizophrenia.

Adult↗

PubMed2004

GSK-3 parameters in postmortem frontal cortex and hippocampus of schizophrenic patients.

The protein kinase glycogen synthase kinase-3 (GSK-3) is highly abundant in brain and involved in signal transduction cascades, particularly during neurodevelopment. We have previously found reduced GSK-3beta mRNA levels, protein levels and GSK-3 total (alpha+beta isoforms) activity in postmortem frontal cortex of schizophrenic patients in the Stanley Medical Research Institute's Brain Collection. To verify and extend these findings, GSK-3 parameters were now measured in the frontal cortex (BA9) and hippocampus obtained from the Rebecca L. Cooper Research Laboratories postmortem brain collection. Fifteen pairs of schizophrenic patients and matched control subjects have been studied. No significant differences in GSK-3alpha and GSK-3beta mRNA levels, GSK-3beta protein levels or total GSK-3 (alpha+beta) activity were found in the frontal cortex of the two diagnostic groups. Hippocampal GSK-3alpha and GSK-3beta mRNA levels were significantly lower (22% and 28%, respectively) in the tissue from the schizophrenic patients compared with the normal controls. Hippocampal GSK-3beta protein levels in the schizophrenic patients were 24% significantly lower than control values only after omission of three outlier subjects. Hippocampal total GSK-3 (alpha+beta) activity in the patients was 31% lower in the schizophrenic patients vs. control subjects. This difference was marginally significant. While our previous data on GSK-3beta in postmortem brain and the recent report that there is impaired AKT1-GSK-3beta signaling in schizophrenia suggest that changes in pathways involving protein kinases such as AKT1 and GSK-3beta in schizophrenia are complex, our present data do not provide strong evidence in support of the involvement of GSK-3beta in schizophrenia. Therefore, further investigation in a greater number of brain samples is warranted to better clarify the possible role of this enzyme in the pathophysiology of schizophrenia.

Enzyme-Linked Immunosorbent Assay↗