期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 41, 页码 16628-16633出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1308706110
关键词
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资金
- National Institutes of Health [NS051195, NS081735, NS080064, MH097446, MH095385, NS037585]
- Simons Foundation [206026]
- MRC
- Sinergia grants
- Canadian Institutes of Health Research postdoctoral grant
- Heart and Stroke Foundation of Canada
- Medical Research Council [MR/K005537/1] Funding Source: researchfish
- MRC [MR/K005537/1] Funding Source: UKRI
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 gamma-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 alpha 2 subunit and GABA transporter 1 (GAT-1) clustering, but increases GABA(A)R alpha 1 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 gamma-power. Collectively, our study provides functional evidence revealing that GABAergic synapses in the prefrontal cortex directly contribute to cognition and.-power.
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