title: Neocortical excitation/inhibition balance in information processing and social dysfunction.
abstract: Severe behavioural deficits in psychiatric diseases such as autism and schizophrenia have been hypothesized to arise from elevations in the cellular balance of excitation and inhibition (E/I balance) within neural microcircuitry. This hypothesis could unify diverse streams of pathophysiological and genetic evidence, but has not been susceptible to direct testing. Here we design and use several novel optogenetic tools to causally investigate the cellular E/I balance hypothesis in freely moving mammals, and explore the associated circuit physiology. Elevation, but not reduction, of cellular E/I balance within the mouse medial prefrontal cortex was found to elicit a profound impairment in cellular information processing, associated with specific behavioural impairments and increased high-frequency power in the 30-80 Hz range, which have both been observed in clinical conditions in humans. Consistent with the E/I balance hypothesis, compensatory elevation of inhibitory cell excitability partially rescued social deficits caused by E/I balance elevation. These results provide support for the elevated cellular E/I balance hypothesis of severe neuropsychiatric disease-related symptoms.
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, California, USA. ofer.yizhar@weizmann.ac.il
authors.forename: Ofer
authors.initials: O
authors.lastname: Yizhar
authors.forename: Lief E
authors.initials: LE
authors.lastname: Fenno
authors.forename: Matthias
authors.initials: M
authors.lastname: Prigge
authors.forename: Franziska
authors.initials: F
authors.lastname: Schneider
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Davidson
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: O'Shea
authors.forename: Vikaas S
authors.initials: VS
authors.lastname: Sohal
authors.forename: Inbal
authors.initials: I
authors.lastname: Goshen
authors.forename: Joel
authors.initials: J
authors.lastname: Finkelstein
authors.forename: Jeanne T
authors.initials: JT
authors.lastname: Paz
authors.forename: Katja
authors.initials: K
authors.lastname: Stehfest
authors.forename: Roman
authors.initials: R
authors.lastname: Fudim
authors.forename: Charu
authors.initials: C
authors.lastname: Ramakrishnan
authors.forename: John R
authors.initials: JR
authors.lastname: Huguenard
authors.forename: Peter
authors.initials: P
authors.lastname: Hegemann
authors.forename: Karl
authors.initials: K
authors.lastname: Deisseroth
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000503:physiopathology; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007858:Learning; D001523:Mental Disorders / Q000503:physiopathology; D051379:Mice; D008959:Models, Neurological; D009043:Motor Activity; D009433:Neural Inhibition / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D055355:Opsins / Q000378:metabolism; D017397:Prefrontal Cortex / Q000502:physiology* / Q000503:physiopathology*; D012559:Schizophrenia / Q000503:physiopathology; D012919:Social Behavior
chemical_list: D055355:Opsins