title: 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 (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.
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA; Center for Integrative Neuroscience, University of California, San Francisco, San Francisco, CA 94143, USA; Sloan-Swartz Center for Theoretical Neurobiology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Kathleen K A
authors.initials: KK
authors.lastname: Cho
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Renee
authors.initials: R
authors.lastname: Hoch
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA; Center for Integrative Neuroscience, University of California, San Francisco, San Francisco, CA 94143, USA; Sloan-Swartz Center for Theoretical Neurobiology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Lee
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA; Center for Integrative Neuroscience, University of California, San Francisco, San Francisco, CA 94143, USA; Sloan-Swartz Center for Theoretical Neurobiology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Tosha
authors.initials: T
authors.lastname: Patel
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: John L R
authors.initials: JL
authors.lastname: Rubenstein
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA; Center for Integrative Neuroscience, University of California, San Francisco, San Francisco, CA 94143, USA; Sloan-Swartz Center for Theoretical Neurobiology, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: vikaas.sohal@ucsf.edu.
authors.forename: Vikaas S
authors.initials: VS
authors.lastname: Sohal
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D003071:Cognition / Q000502:physiology*; D004195:Disease Models, Animal; D065818:Gamma Rhythm / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007395:Interneurons / Q000502:physiology*; D008297:Male; D051379:Mice; D010320:Parvalbumins / Q000378:metabolism; D017397:Prefrontal Cortex / Q000502:physiology / Q000503:physiopathology*; D012559:Schizophrenia / Q000503:physiopathology
chemical_list: C501120:Dlx5 protein, mouse; C100597:Dlx6 protein, mouse; D018398:Homeodomain Proteins; D010320:Parvalbumins