Contribution of mGluR5 to pathophysiology in a mouse model of human chromosome 16p11.2 microdeletion
Di Tian1, Laura J Stoppel2, Arnold J Heynen2
11] 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.
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.
Insights
Human chromosome 16p11.2 microdeletion, a common autism gene variation, impairs hippocampus-dependent memory. Targeting metabotropic glutamate receptor 5 (mGluR5) with a specific drug reversed these cognitive deficits in mice.
Area of Science:
- Neurogenetics
- Synaptic Plasticity
- Autism Spectrum Disorder Pathophysiology
Background:
- The 16p11.2 microdeletion is the most frequent copy number variation associated with autism spectrum disorder.
- The precise synaptic mechanisms underlying cognitive deficits in 16p11.2 microdeletion remain poorly understood.
Purpose of the Study:
- To investigate the synaptic pathophysiology in a mouse model of human chromosome 16p11.2 microdeletion.
- To determine the role of metabotropic glutamate receptor 5 (mGluR5) signaling in cognitive impairments associated with this microdeletion.
- To evaluate the therapeutic potential of targeting mGluR5 for cognitive deficits.
Main Methods:
- Utilized a mouse model harboring the 16p11.2 genetic deficiency.
- Assessed synaptic plasticity and protein synthesis in hippocampal tissues.
- Evaluated hippocampus-dependent memory performance.
- Administered chronic treatment with a negative allosteric modulator of mGluR5.
Main Results:
- Significant alterations in mGluR5-dependent synaptic plasticity and protein synthesis were observed in the hippocampus of affected mice.
- Mice exhibited impaired hippocampus-dependent memory.
- Chronic treatment with an mGluR5 negative allosteric modulator successfully reversed the observed cognitive deficits.
Conclusions:
- The 16p11.2 microdeletion impacts synaptic function and memory through mGluR5-dependent pathways.
- Targeting mGluR5 represents a promising therapeutic strategy for cognitive impairments in individuals with 16p11.2 microdeletion and potentially other forms of autism.
