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Hippocampal interneurons are abnormal in schizophrenia.

ABSTRACT: The cellular substrate of hippocampal dysfunction in schizophrenia remains unknown. We tested the hypothesis that hippocampal interneurons are abnormal in schizophrenia, but that the total number of hippocampal neurons in the pyramidal cell layer is normal.We collected whole hippocampal specimens of 13 subjects with schizophrenia and 20 matched healthy control subjects to study the number of all neurons, the somal volume of neurons, the number of somatostatin- and parvalbumin-positive interneurons and the messenger RNA levels of somatostatin, parvalbumin and glutamic acid decarboxylase 67.The total number of hippocampal neurons in the pyramidal cell layer was normal in schizophrenia, but the number of somatostatin- and parvalbumin-positive interneurons, and the level of somatostatin, parvalbumin and glutamic acid decarboxylase mRNA expression were reduced.The study provides strong evidence for a specific defect of hippocampal interneurons in schizophrenia and has implications for emerging models of hippocampal dysfunction in schizophrenia.

SUBMITTER: Konradi C

PROVIDER: S-EPMC3159834 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Hippocampal interneurons are abnormal in schizophrenia.

Konradi Christine C Yang C Kevin CK Zimmerman Eric I EI Lohmann Kathryn M KM Gresch Paul P Pantazopoulos Harry H Berretta Sabina S Heckers Stephan S

Schizophrenia research 20110713 1-3

<h4>Objective</h4>The cellular substrate of hippocampal dysfunction in schizophrenia remains unknown. We tested the hypothesis that hippocampal interneurons are abnormal in schizophrenia, but that the total number of hippocampal neurons in the pyramidal cell layer is normal.<h4>Methods</h4>We collected whole hippocampal specimens of 13 subjects with schizophrenia and 20 matched healthy control subjects to study the number of all neurons, the somal volume of neurons, the number of somatostatin- a ...[more]

PMID: 21745723

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Project description:UNLABELLED:Although synapsins regulate GABA release, it is unclear which synapsin isoforms are involved. We identified the synapsin isoforms that regulate GABA release via rescue experiments in cultured hippocampal neurons from synapsin I, II, and III triple knock-out (TKO) mice. In situ hybridization indicated that five different synapsin isoforms are expressed in hippocampal interneurons. Evoked IPSC amplitude was reduced in TKO neurons compared with triple wild-type neurons and was rescued by introducing any of the five synapsin isoforms. This contrasts with hippocampal glutamatergic terminals, where only synapsin IIa rescues the TKO phenotype. Deconvolution analysis indicated that the duration of GABA release was prolonged in TKO neurons and this defect in release kinetics was rescued by each synapsin isoform, aside from synapsin IIIa. Because release kinetics remained slow, whereas peak release rate was rescued, there was a 2-fold increase in GABA release in TKO neurons expressing synapsin IIIa. TKO neurons expressing individual synapsin isoforms showed normal depression kinetics aside from more rapid depression in neurons expressing synapsin IIIa. Measurements of the cumulative amount of GABA released during repetitive stimulation revealed that the rate of mobilization of vesicles from the reserve pool to the readily releasable pool and the size of the readily releasable pool of GABAergic vesicles were unaffected by synapsins. Instead, synapsins regulate release of GABA from the readily releasable pool, with all isoforms aside from synapsin IIIa controlling release synchrony. These results indicate that synapsins play fundamentally distinct roles at different types of presynaptic terminals. SIGNIFICANCE STATEMENT:Synapsins are a family of proteins that regulate synaptic vesicle (SV) trafficking within nerve terminals. Here, we demonstrate that release of the inhibitory neurotransmitter GABA is supported by many different synapsin types. This contrasts with the release of other neurotransmitters, which typically is supported by only one type of synapsin. We also found that synapsins serve to synchronize the release of GABA in response to presynaptic action potentials, which is different from the synapsin-dependent trafficking of SVs in other nerve terminals. Our results establish that different synapsins play fundamentally different roles at nerve terminals releasing different types of neurotransmitters. This is an important clue to understanding how neurons release their neurotransmitters, a process essential for normal brain function.

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Hippocampal interneurons are abnormal in schizophrenia.

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Hippocampal interneurons are abnormal in schizophrenia.

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