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Myosin Va Brain-Specific Mutation Alters Mouse Behavior and Disrupts Hippocampal Synapses.
Swarna Pandian1,2,3, Jian-Ping Zhao1, Yasunobu Murata1
1Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
Eneuro
|November 24, 2020
Summary
Mutant Myosin Va (MyoVa) in mice disrupts synaptic transport, leading to anxiety and memory deficits. This Flailer mouse model reveals how impaired transport impacts brain function and causes neuropsychiatric disorder symptoms.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Myosin Va (MyoVa) is a motor protein crucial for transporting cargo in neurons, particularly to the dendritic spine's postsynaptic density (PSD).
- Mutations in MyoVa are linked to severe human neurological disorders, highlighting its importance in brain function.
Purpose of the Study:
- To characterize the Flailer (Flr) mutant mouse, which expresses a dominant-negative form of MyoVa in the central nervous system (CNS).
- To investigate how this mutant MyoVa disrupts synaptic transport and its downstream effects on synaptic function, behavior, and brain development.
Main Methods:
- Generated a mouse model (Flailer) with a myo5a mutation causing high levels of a dominant-negative MyoVa protein in the CNS.
- Assessed synaptic transport, postsynaptic density (PSD) formation, dendritic spine maturation, and behavioral abnormalities in Flr mice.
- Examined mGluR-dependent long-term depression (LTD) in the mutant mice.
Main Results:
- Flr protein acts as a dominant-negative MyoVa, blocking cargo transport to the PSD.
- Flr mice exhibit defective synaptic component transport, reduced mature dendritic spines, and impaired mGluR-dependent LTD.
- These synaptic deficits correlate with abnormal behaviors, including anxiety and memory deficits, resembling symptoms of obsessive-compulsive disorder and autism spectrum disorder (ASD).
Conclusions:
- The Flailer mouse provides a valuable model for studying the consequences of disrupted synaptic transport and impaired LTD.
- This model can elucidate how these synaptic dysfunctions contribute to the development of neuropsychiatric disorders.
- Understanding these mechanisms is crucial for analyzing brain development, wiring, and function in the context of neurological diseases.
