期刊
NEURON
卷 85, 期 6, 页码 1332-1343出版社
CELL PRESS
DOI: 10.1016/j.neuron.2015.02.019
关键词
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资金
- Staglin Family and International Mental Health Research Organization, NIMH [R00MH085946, R01MH100292]
- Alfred P. Sloan Foundation
- NIH Office of the Director [DP2MH100011]
- NIH training grant [T32MH89920]
- Brain and Behavior Foundation
- NIMH [R37MH049428]
Abnormalities in GABAergic interneurons, particularly fast-spiking interneurons (FSINs) that generate gamma (gamma; similar to 30-120 Hz) oscillations, are hypothesized to disrupt prefrontal cortex (PFC)-dependent cognition in schizophrenia. Although gamma rhythms are abnormal in schizophrenia, it remains unclear whether they directly influence cognition. Mechanisms underlying schizophrenia's typical post-adolescent onset also remain elusive. We addressed these issues using mice heterozygous for Dlx5/6, which regulate GABAergic interneuron development. In Dlx5/6(+/-) mice, FSINs become abnormal following adolescence, coinciding with the onset of cognitive inflexibility and deficient task-evoked gamma oscillations. Inhibiting PFC interneurons in control mice reproduced these deficits, whereas stimulating them at gamma-frequencies restored cognitive flexibility in adult Dlx5/6(+/-) mice. These pro-cognitive effects were frequency specific and persistent. These findings elucidate a mechanism whereby abnormal FSIN development may contribute to the post-adolescent onset of schizophrenia endophenotypes. Furthermore, they demonstrate a causal, potentially therapeutic, role for PFC interneuron-driven gamma oscillations in cognitive domains at the core of schizophrenia.
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