November 23, 2020

Myosin Va Brain-Specific Mutation Alters Mouse Behavior and Disrupts Hippocampal Synapses

ABSTRACTMyosin Va (MyoVa) is a plus-end filamentous-actin motor protein that is highly and broadly expressed in the vertebrate body, including in the nervous system. In excitatory neurons MyoVa transports cargo toward the tip of the dendritic spine, where the post-synaptic density (PSD) is formed and maintained. MyoVa mutations in humans cause neurological dysfunction, mental retardation, hypomelanation and death in infancy or childhood. Here we characterize the Flailer (Flr) mutant mouse, which is homozygous for a myo5a mutation that drives high levels of mutant MyoVa (Flr protein) specifically in the CNS. Flr protein functions as a dominant-negative MyoVa, sequestering cargo and blocking its transport to the PSD. Flr mice have early seizures and mild ataxia, but mature and breed normally. Flr mice display several abnormal behaviors known to be associated with brain regions that show high expression of Flr protein. Flr mice are defective in the transport of synaptic components to the PSD and in mGluR-dependent LTD and have a reduced number of mature dendritic spines. The synaptic and behavioral abnormalities of Flr mice result in an anxiety/autism spectrum disorder (ASD)/obsessive compulsive-like phenotype similar to that of other mouse mutants with similar abnormalities. Because of the dominant-negative nature of the Flr protein, the Flr mouse offers a powerful system for the analysis of how the disruption of synaptic transport and lack of LTD can alter synaptic function, development and wiring of the brain and result in symptoms that characterize many neuropsychiatric disorders.SIGNIFICANCE STATEMENT Here we characterize a mutant mouse homozygous for a Myosin Va mutation named Flailer. The Flailer mutation generates a dominant-negative MyoVa transport motor protein that sequesters synaptic cargo and blocks synaptic transport, thereby resulting in an absence of LTD and in abnormal behaviors similar to those seen anxiety/Autism Spectrum disorders. We propose that the Flailer mutant can be used as a model to study how the absence of LTD disrupts brain connectivity and behavior. Moreover, by using the Flailer mutation together with gene editing technologies it should be possible to target specific brain areas to remove the mutation and recover MyoVa function, thereby interrogating the role of a specific brain region in the control of a particular behavior.Competing Interest StatementThe authors have declared no competing interest.View Full Text

 bioRxiv Subject Collection: Neuroscience

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