Gamma Rhythms Link Prefrontal Interneuron Dysfunction with Cognitive Inflexibility in Dlx5/6+/- Mice

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.