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

Neuron. 2015 Mar 18;85(6):1332-43. doi: 10.1016/j.neuron.2015.02.019. Epub 2015 Mar 5.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal
  • Cognition / physiology*
  • Disease Models, Animal
  • Gamma Rhythm / physiology*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Interneurons / physiology*
  • Male
  • Mice
  • Parvalbumins / metabolism
  • Prefrontal Cortex / physiology
  • Prefrontal Cortex / physiopathology*
  • Schizophrenia / physiopathology


  • Dlx5 protein, mouse
  • Dlx6 protein, mouse
  • Homeodomain Proteins
  • Parvalbumins