Differences in the subregional and cellular distribution of GABAA receptor binding in the hippocampal formation of schizophrenic brain

Abstract

Recent postmortem studies have reported a marked upregulation of GABAA receptor binding activity in the anterior cingulate and prefrontal cortices of schizophrenic subjects. Because the hippocampal formation is a key corticolimbic region that has also been implicated by both postmortem and brain imaging studies in the pathophysiology of this disorder, the current report has sought to determine whether alterations of GABAA receptor binding might also be detected in this region from 15 normal controls and 8 schizophrenic subjects. Using a low resolution autoradiographic approach, the results show a significant increase of specific GABAA receptor binding activity in the area dentata (granule cell layer), CA4, CA3 (str. oriens, str. pyramidale), subiculum, and presubiculum of the schizophrenic group. The magnitude of the increase was greatest in CA3 and lowest in the CA1 sector. When high resolution analyses were performed on emulsion‐coverslip preparations, a modest increase of binding (43%, P = 0.05) was observed on pyramidal, but not non‐pyramidal neurons in sector CA1. Rather unexpectedly, GABAA binding in sector CA3 was not significantly different on pyramidal cells, but was almost three‐fold higher (P = 0.015) on non‐pyramidal neurons of the schizophrenic group. There was no relationship of age or the postmortem interval to the parameters showing significant changes in the schizophrenic group. Moreover, patients both with and without neuroleptic exposure showed upregulation of GABAA receptor binding activity. Taking together the rather modest increase of binding activity in CA1 and the more marked upregulation in CA3, as well as the differential changes on pyramidal neurons of CA1 vs. non‐pyramidal neurons in CA3, the findings reported here are consistent with the possibility that a disturbance of brain development could have occurred either perinatally or perhaps even well into the postnatal period, and have given rise to discreet subregional and cellular alterations of disinhibitory GABAergic modulation in sector CA3 of schizophrenics. Overall, the data reported here provide further evidence that alterations of GABAergic activity may occur in the hippocampal formation of schizophrenic patients. © 1996 Wiley‐Liss, Inc.

Targeting the Hippocampal Mossy Fiber Synapse for the Treatment of Psychiatric Disorders

“…Increased frequency of dentate granule cells with basal dendrites [149] Neurotransmitter receptor Glutamate Decrease in [ 3 H]kainate binding [115] Decreases in AMPA receptor subunit GluR1 and GluR2 mRNAs (no significant change in CA1) [116] Decrease in kainate receptor subunits GluR6 and KA2 mRNAs (no significant change in CA1) [117] Decrease in NMDAR receptor subunit NR1mRNAs (no significant change in CA1) [118,120] Acetylcholine Decrease in [ 125 l]-α-bungarotoxin (nicotinic ligand) binding (no significant change in CA1) [121] Decrease in [ 3 H]pirenzepine (muscarinic ligand) binding [122] GABA Increase in [ 3 H]muscimol (GABA A ligand) binding [113] Decrease in GABA B immunoreactive cells [119] Noradrenaline Decrease in [ 125 I]iodopindolol (βreceptor ligand) binding [114] Hormone receptor Decrease in glucocorticoid receptor mRNA [191] Decrease in estrogen receptor α mRNA (dentate gyrus-specific change) [192] Presynaptic protein Decrease in synaptophysin immunoreactivity (no significant change in CA1) [123] Increase in synaptophysin immunoreactivity [124] Decrease in SNAP-25 immunoreactivity [124] Neurodevelopment/Plasticity Decrease in PSA-NCAM immunoreactive cell in hilus [193] Decrease in [ 3 H]forskolin (adenylate cyclase ligand) binding (dentate gyrus-specific change) [194] Decrease in density of reelin immunoreactive cells [136] Increase in retinoic acid receptor α immunoreactive granule cells [138] Decrease in calbindin mRNA (laser captured dentate gyrus) [125] Decrease in reelin mRNA-expressing molecular layer cells [137] Decrease in cells with proliferation maker Ki-67 immunoreactivity…”

“…Studies on the postmortem brain revealed substantial abnormalities in the dentate gyrus in patients with schizophrenia (Table 1). Those include changes in expression of various transmitter receptors [113][114][115][116][117][118][119][120][121][122], other synaptic proteins [123,124], and proteasome, ubiquitin, and mitochondrial genes [125], suggesting profound functional defects of the dentate gyrus in schizophrenia. The mossy fiber system also has some abnormalities in synaptic structure [126], density of synaptic terminals [127], and expression of presynaptic proteins [128].…”

Neurochemical Changes in LPA1 Receptor Deficient Mice – A Putative Model of Schizophrenia

“…GABA interneurones provide inhibitory and disinhibitory modulation of cortical and hippocampal circuits and gate sensory information within the corticolimbic system, which is abnormal in schizophrenia (14). There are reported decreases in the number of GABA-containing non-pyramidal cells (14), the GABA uptake site (27) and [ 3 H]muscimol binding (28) in the hippocampus of schizophrenics. Therefore, a reduction in GABA release is consistent with a schizophrenia-like phenotype.…”

GABAergic dysfunction in schizophrenia: new treatment strategies on the horizon

“…Benes et al 1992;Akbarian et al 1995a,b;Guidotti et al 2000;Volk et al 2000;Woo et al 2004;Veldic et al 2005↓Reelin Fatemi et al 2000Guidotti et al 2000;Eastwood and Harrison 2003;Veldic et al 2004;Abdolmaleky et al 2005↓GAT-1 Woo et al 1998↓Parvalbumin Lewis et al 2004↓NR2A Woo et al 2004 (2) The postsynaptic component: compensatory alterations in pyramidal neurons? (a) GABA A receptor upregulation ↑ 3 H muscimol binding Hanada et al 1987;Benes et al 1992Benes et al , 1996aDean et al 2001 ↑GABA A α 1 ,α 2 ,α 5 mRNAs Impagnatiello et al 1998;Lewis et al 2004 ↑GABA A α 1 ,α 2 ,α 5 proteins Ishikawa et al 2004;Lewis et al 2004 (b) Neuropil hypoplasticity ↓Dendritic spines Glantz and Lewis, 2001;Rosoklija et al 2000 GAD Glutamic acid decarboxylase, GAT1 GABA membrane transporter 1, NR2AN-methyl-D-aspartate receptor subunit 2 A The presynaptic component as a primary defect of cortical GABAergic neurons in SZ and BP disorders…”