title: Disruption of mGluR5 in parvalbumin-positive interneurons induces core features of neurodevelopmental disorders.
abstract: Alterations in glutamatergic transmission onto developing GABAergic systems, in particular onto parvalbumin-positive (Pv(+)) fast-spiking interneurons, have been proposed as underlying causes of several neurodevelopmental disorders, including schizophrenia and autism. Excitatory glutamatergic transmission, through ionotropic and metabotropic glutamate receptors, is necessary for the correct postnatal development of the Pv(+) GABAergic network. We generated mutant mice in which the metabotropic glutamate receptor 5 (mGluR5) was specifically ablated from Pv(+) interneurons postnatally, and investigated the consequences of such a manipulation at the cellular, network and systems levels. Deletion of mGluR5 from Pv(+) interneurons resulted in reduced numbers of Pv(+) neurons and decreased inhibitory currents, as well as alterations in event-related potentials and brain oscillatory activity. These cellular and sensory changes translated into domain-specific memory deficits and increased compulsive-like behaviors, abnormal sensorimotor gating and altered responsiveness to stimulant agents. Our findings suggest a fundamental role for mGluR5 in the development of Pv(+) neurons and show that alterations in this system can produce broad-spectrum alterations in brain network activity and behavior that are relevant to neurodevelopmental disorders.
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Barnes
authors.affiliation: Computational Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Pinto-Duarte
authors.affiliation: Computational Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kappe
authors.affiliation: Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Zembrzycki
authors.affiliation: Computational Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Metzler
authors.affiliation: Computational Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Mukamel
authors.affiliation: Computational Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lucero
authors.affiliation: Computational Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Computational Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.|Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA, USA.|Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Sejnowski
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Markou
authors.affiliation: Computational Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Behrens
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism / Q000473:pathology; D007395:Interneurons / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D065886:Neurodevelopmental Disorders / Q000378:metabolism* / Q000473:pathology*; D010320:Parvalbumins / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*
chemical_list: D010320:Parvalbumins; D018092:Kainic Acid Receptors; D018094:Receptors, Metabotropic Glutamate