Disrupting the clustering of GABA_Areceptor α2 subunits in the frontal cortex leads to reduced γ-power and cognitive deficits

Abstract

In schizophrenia, cognitive dysfunction is highly predictive of poor patient outcomes and is not responsive to current medications. Postmortem studies have suggested that cognitive deficits in schizophrenia are correlated with modifications in the number and size of inhibitory synapses. To test if these modifications lead to cognitive deficits, we have created a dominant-negative virus [adeno-associated (AAV)-DN1] that disrupts the clustering of γ-aminobutyric acid type A receptors (GABA A Rs) at postsynaptic inhibitory specializations. When injected into the frontal cortex of mice, AAV-DN1 impairs GABA A R α2 subunit and GABA transporter 1 (GAT-1) clustering, but increases GABA A R α1 subunit clustering on the perisomatic region, with no influence on axon-initial segment clustering. Mice expressing AAV-DN1 have prepulse inhibition deficits and impairments in working memory. Significantly, these behavioral deficits are paralleled by a reduction in electroencephalography γ-power. Collectively, our study provides functional evidence revealing that GABAergic synapses in the prefrontal cortex directly contribute to cognition and γ-power. In schizophrenia, the classical positive and negative symptoms are accompanied by striking cognitive deficits, and notably, the cognitive deficits are not ameliorated by conventional antipsychotic medications (1-3). Thus, understanding the molecular basis of these deficits is key to development of more efficacious treatments. In addition to modifications in the dopaminergic system, there is compelling evidence that modifications in signaling by γ-aminobutyric acid receptors (GABA A R) contributes to the cognitive deficits in schizophrenia. GABA A Rs are the principle mediators of fast synaptic inhibition in the brain and are pentameric heteroligomers that are principally assembled from α1-6, β1-3, γ1-3, and δ subunits (4). Within the cortex, GABA A Rs containing α2 subunits are enriched on the axoninitial segments (AIS) and perisomatic regions of neurons, where their activation has been shown to underlie oscillatory activity and cognition (5, 6).Postmortem analysis has revealed increased levels of α2 subunit immunoreactivity on the AIS of principal cortical neurons in schizophrenia and parallel deficits in the number of GABA transporter (GAT-1) positive presynaptic elements. However, whether these modifications in inhibitory synapse structure contribute to the cognitive deficits of schizophrenia remains unknown. To address this issue we have used virally encoded dominantnegative reagents to disrupt the function of inhibitory synapses containing α2 subunits in the cortex of mice. This resulted in prepulse inhibition deficits and impairments in working memory that were paralleled by a reduction in electroencephalography γ-power. Thus, α2 subunit-containing GABA A Rs are important determinants of cognition, and selectively potentiating their activity may be beneficial in improving the outcome of patients with schizophrenia. Results Creation of Dominant Negative Reagents to Disrupt the ...

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