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Lamina-specific alterations in cortical GABA(A) receptor subunit expression in schizophrenia.

ABSTRACT: Dysfunction of the dorsolateral prefrontal cortex (DLPFC) in schizophrenia is associated with lamina-specific alterations in particular subpopulations of interneurons. In pyramidal cells, postsynaptic ?-aminobutyric acid (GABA(A)) receptors containing different ? subunits are inserted preferentially in distinct subcellular locations targeted by inputs from specific interneuron subpopulations. We used in situ hybridization to quantify the laminar expression of ?1, ?2, ?3, and ?5 subunit, and of ?1-3 subunit, mRNAs in the DLFPC of schizophrenia, and matched normal comparison subjects. In subjects with schizophrenia, mean GABA(A) ?1 mRNA expression was 17% lower in layers 3 and 4, ?2 expression was 14% higher in layer 2, ?5 expression was 15% lower in layer 4, and ?3 expression did not differ relative to comparison subjects. The mRNA expression of ?2, which preferentially assembles with ?1 subunits, was also 20% lower in layers 3 and 4, whereas ?1 and ?3 mRNA levels were not altered in schizophrenia. These expression differences were not attributable to medication effects or other potential confounds. These findings suggest that GABA neurotransmission in the DLPFC is altered at the postsynaptic level in a receptor subunit- and layer-specific manner in subjects with schizophrenia and support the hypothesis that GABA neurotransmission in this illness is predominantly impaired in certain cortical microcircuits.

SUBMITTER: Beneyto M

PROVIDER: S-EPMC3077427 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Lamina-specific alterations in cortical GABA(A) receptor subunit expression in schizophrenia.

Beneyto Monica M Abbott Andrew A Hashimoto Takanori T Lewis David A DA

Cerebral cortex (New York, N.Y. : 1991) 20100915 5

Dysfunction of the dorsolateral prefrontal cortex (DLPFC) in schizophrenia is associated with lamina-specific alterations in particular subpopulations of interneurons. In pyramidal cells, postsynaptic γ-aminobutyric acid (GABA(A)) receptors containing different α subunits are inserted preferentially in distinct subcellular locations targeted by inputs from specific interneuron subpopulations. We used in situ hybridization to quantify the laminar expression of α1, α2, α3, and α5 subunit, and of β ...[more]

PMID: 20843900

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Project description:Disturbed cortical ?-aminobutyric acid (GABA) neurotransmission in schizophrenia is evident from lamina- and cell type- specific alterations in presynaptic markers. In the dorsolateral prefrontal cortex (DLPFC), these alterations include lower transcript expression of glutamic acid decarboxylase (GAD67) and somatostatin (SST), a neuropeptide expressed in the Martinotti subpopulation of GABA neurons whose axons innervate the distal apical dendrites of pyramidal neurons. However, whether the alterations in SST-containing interneurons are associated with changes in post-synaptic receptors for SST has not been examined. Thus, we used in situ hybridization to quantify the mRNA expression levels of SST receptors subtype 1 (SSTR1) and subtype 2 (SSTR2) in DLPFC area 9 from 23 matched pairs of subjects with schizophrenia and normal comparison subjects. We also assessed the effects of potential confounding variables within the human subjects and in brain specimens from macaque monkeys with long term exposure to antipsychotic drugs. SSTR1 mRNA levels did not differ between subject groups. In contrast, mean cortical SSTR2 mRNA levels were significantly 19% lower in the subjects with schizophrenia. Laminar and cellular level analyses revealed that lower SSTR2 mRNA levels were localized to pyramidal cells in cortical layers 5-6. Expression of SSTR2 mRNA did not differ between monkeys exposed chronically to high doses of haloperidol or olanzapine and control animals, or between subjects with schizophrenia on or off antipsychotic medications at the time of death. However, levels of SSTR2 mRNA were significantly 37.6% lower in monkeys exposed chronically to low dose haloperidol, suggesting that the lower levels of SSTR2 mRNA selectively in pyramidal neurons in DLPFC layers 5-6 in schizophrenia should be interpreted with caution. In concert with prior findings of lower SST mRNA expression in the same subjects, the results of this study suggest the convergence of pre- and post-synaptic mechanisms to reduce inhibitory inputs to pyramidal neurons in the infragranular layers of the DLPFC.

Project description:ObjectiveDeficits in working memory and cognitive control in schizophrenia are associated with impairments in prefrontal cortical function, including altered gamma band oscillations. These abnormalities are thought to reflect a deficiency in the synchronization of pyramidal cell activity that is dependent, in part, on gamma-aminobutyric acid (GABA) neurotransmission through GABA type A (GABA(A)) receptors containing alpha(2) subunits. The authors conducted a proof-of-concept clinical trial designed to test the hypothesis that a novel compound with relatively selective agonist activity at GABA(A) receptors containing alpha(2) subunits would improve cognitive function and gamma band oscillations in individuals with schizophrenia.MethodParticipants were male subjects (N=15) with chronic schizophrenia who were randomly assigned to receive 4 weeks of treatment with the study drug MK-0777, a benzodiazepine-like agent with selective activity at GABA(A) receptors containing alpha(2) or alpha(3) subunits, or a matched placebo in a double-blind fashion. Outcome measures were the Brief Psychiatric Rating Scale (BPRS), Repeatable Battery for the Assessment of Neuropsychological Status, three tests of working memory and/or cognitive control (N-back, AX Continuous Performance Test, and Preparing to Overcome Prepotency), and EEG measures of gamma band oscillations induced during the Preparing to Overcome Prepotency task.ResultsCompared with placebo, the MK-0777 compound was associated with improved performance on the N-back, AX Continuous Performance Test, and Preparing to Overcome Prepotency tasks. The compound was also associated with increased frontal gamma band power during the Preparing to Overcome Prepotency task. No effects of the MK-0777 compound were detected in BPRS or Repeatable Battery for the Assessment of Neuropsychological Status scores, with the exception of improvement on the Repeatable Battery for the Assessment of Neuropsychological Status delayed memory index. The MK-0777 agent was well-tolerated.ConclusionsThese findings provide preliminary support for the hypothesis that enhanced GABA activity at alpha(2) subunit containing GABA(A) receptors improves behavioral and electrophysiological measures of prefrontal function in individuals with schizophrenia.

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Lamina-specific alterations in cortical GABA(A) receptor subunit expression in schizophrenia.

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Lamina-specific alterations in cortical GABA(A) receptor subunit expression in schizophrenia.

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