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Gamma rhythms link prefrontal interneuron dysfunction with cognitive inflexibility in Dlx5/6+/− mice
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    Abnormalities in GABAergic interneurons, particularly fast-spiking interneurons (FSINs) that generate gamma (γ; ∼30-120 Hz) oscillations, are hypothesized to disrupt prefrontal cortex (PFC)-dependent cognition in schizophrenia. Although γ 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 γ oscillations. Inhibiting PFC interneurons in control mice reproduced these deficits, whereas stimulating them at γ-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 γ oscillations in cognitive domains at the core of schizophrenia.

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  • Funding:
    DP2 MH100011/MH/NIMH NIH HHS/United States
    DP2MH100011/DP/NCCDPHP CDC HHS/United States
    R00 MH085946/MH/NIMH NIH HHS/United States
    R00MH085946/MH/NIMH NIH HHS/United States
    R01 MH100292/MH/NIMH NIH HHS/United States
    R01MH100292/MH/NIMH NIH HHS/United States
    R37 MH049428/MH/NIMH NIH HHS/United States
    R37MH049428/MH/NIMH NIH HHS/United States
    T32MH89920/MH/NIMH NIH HHS/United States
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