Contribution of mGluR5 to pathophysiology in a mouse model of human chromosome 16p11.2 microdeletion

Di Tian; Laura J Stoppel; Arnold J Heynen; Lothar Lindemann; Georg Jaeschke; Alea A Mills; Mark F Bear

doi:10.1038/nn.3911

Contribution of mGluR5 to pathophysiology in a mouse model of human chromosome 16p11.2 microdeletion

Nat Neurosci. 2015 Feb;18(2):182-4. doi: 10.1038/nn.3911. Epub 2015 Jan 12.

Authors

Di Tian¹, Laura J Stoppel², Arnold J Heynen², Lothar Lindemann³, Georg Jaeschke³, Alea A Mills⁴, Mark F Bear²

Affiliations

¹ 1] Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. [2] The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. [3] Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. [4] Department of Pathology and Laboratory Medicine, Developmental Neuroscience Program, The Saban Research Institute, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
² 1] Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. [2] The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. [3] Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
³ Pharmaceuticals Division, F. Hoffmann-La Roche, Basel, Switzerland.
⁴ Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.

PMID: 25581360
PMCID: PMC4323380
DOI: 10.1038/nn.3911

Abstract

Human chromosome 16p11.2 microdeletion is the most common gene copy number variation in autism, but the synaptic pathophysiology caused by this mutation is largely unknown. Using a mouse with the same genetic deficiency, we found that metabotropic glutamate receptor 5 (mGluR5)-dependent synaptic plasticity and protein synthesis was altered in the hippocampus and that hippocampus-dependent memory was impaired. Notably, chronic treatment with a negative allosteric modulator of mGluR5 reversed the cognitive deficit.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autistic Disorder / genetics
Autistic Disorder / metabolism
Autistic Disorder / physiopathology*
Behavior, Animal / drug effects
Behavior, Animal / physiology
Chromosome Deletion
Chromosome Disorders / genetics
Chromosome Disorders / metabolism
Chromosome Disorders / physiopathology*
Chromosomes, Human, Pair 16 / genetics
Chromosomes, Human, Pair 16 / metabolism
Chromosomes, Mammalian
Disease Models, Animal
Hippocampus / metabolism
Hippocampus / physiopathology*
Imidazoles / pharmacology*
Intellectual Disability / genetics
Intellectual Disability / metabolism
Intellectual Disability / physiopathology*
Male
Memory Disorders / drug therapy
Memory Disorders / metabolism
Memory Disorders / physiopathology*
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neuronal Plasticity / drug effects
Neuronal Plasticity / genetics
Neuronal Plasticity / physiology
Pyridines / pharmacology*
Receptor, Metabotropic Glutamate 5 / genetics
Receptor, Metabotropic Glutamate 5 / metabolism
Receptor, Metabotropic Glutamate 5 / physiology*
Signal Transduction / drug effects
Signal Transduction / genetics
Signal Transduction / physiology

Substances

2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine
Imidazoles
Pyridines
Receptor, Metabotropic Glutamate 5

Supplementary concepts

16p11.2 Deletion Syndrome

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding