Gamma rhythms link prefrontal interneuron dysfunction with cognitive inflexibility in Dlx5/6(+/-) mice.

ABSTRACT: Abnormalities in GABAergic interneurons, particularly fast-spiking interneurons (FSINs) that generate gamma (?; ?30-120 Hz) oscillations, are hypothesized to disrupt prefrontal cortex (PFC)-dependent cognition in schizophrenia. Although ? 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 ? oscillations. Inhibiting PFC interneurons in control mice reproduced these deficits, whereas stimulating them at ?-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 ? oscillations in cognitive domains at the core of schizophrenia.

SUBMITTER: Cho KK 

PROVIDER: S-EPMC4503262 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature