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.

Chronic chemogenetic activation of forebrain excitatory neurons in postnatal life evokes long-lasting changes in mood-related behavior

“…Preclinical genetic models targeting signaling pathways downstream to Gq (PLC-β1 -/mice) exhibit enhanced schizophrenia-like behavior 95 . Further, loss of function of the Gq-coupled mGluR5 receptor in parvalbumin-positive interneurons increased both compulsive behavior and aberrant sensorimotor gating 96 . It is important to note that PPI deficits are also common across various other neuropsychiatric conditions, in addition to schizophrenia 97,98 .…”

Enhanced Neuronal Activity in the Medial Prefrontal Cortex during Social Approach Behavior

“…We addressed this issue in the present study by examining the activity of mPFC neurons in mice during a three-chamber test (Crawley, 2004), which is widely used to measure social dysfunction in animal models of ASDs (Won et al, 2012;Huang et al, 2014;Chung et al, 2015), schizophrenia (Del Pino et al, 2013;Nguyen et al, 2014), and other neurodevelopmental disorders (Grayton et al, 2013;Barnes et al, 2015). In the three-chamber test, a subject mouse is allowed to explore two opposing chambers containing another mouse (social stimulus) or an inanimate object (nonsocial stimulus), and the relative amount of time spent exploring the social versus nonsocial target is used as an index of social preference.…”

Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders

“…Deletion of mGlu 5 from parvalbumin expressing neurons is sufficient to induce cognitive and sensorimotor gating deficits in rodents (Barnes et al, 2015), and administration of mGlu 5 PAMs in adolescence prevented the appearance of delayed cognitive deficits in a developmental model of schizophrenia (Clifton et al, 2013). These findings suggest the exciting possibility of a preventative role for mGlu 5 PAM treatment in the development of schizophrenia, and further work will be important to evaluate these findings.…”