Disruption of mGluR5 in parvalbumin-positive interneurons induces core features of neurodevelopmental disorders

被引:64
作者
Barnes, S. A. [1 ]
Pinto-Duarte, A. [2 ]
Kappe, A. [2 ]
Zembrzycki, A. [3 ]
Metzler, A. [2 ]
Mukamel, E. A. [2 ]
Lucero, J. [2 ]
Wang, X. [2 ]
Sejnowski, T. J. [2 ,4 ,5 ]
Markou, A. [1 ]
Behrens, M. M. [2 ]
机构
[1] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA
[2] Salk Inst Biol Studies, Computat Neurobiol Lab, La Jolla, CA 92037 USA
[3] Salk Inst Biol Studies, Mol Neurobiol Lab, La Jolla, CA 92037 USA
[4] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA
[5] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA
基金
美国国家科学基金会;
关键词
GLUTAMATE-RECEPTOR; 5; AUDITORY HALLUCINATION SYMPTOMS; LONG-TERM POTENTIATION; PREPULSE INHIBITION; NMDA RECEPTORS; MICE LACKING; OSCILLATORY ACTIVITY; RECOGNITION MEMORY; GAMMA-OSCILLATIONS; SPATIAL MEMORY;
D O I
10.1038/mp.2015.113
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1161 / 1172
页数:12
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