Functions of caldendrin in sensory neurons

About This Grant

Project Summary Hypersensitivity to touch is common in neurodevelopmental disorders including autism spectrum disorder (ASD). Individuals with ASD can have aversive responses to certain textures or human touch, which can lead to emotional distress, social withdrawal, and difficulties accomplishing everyday tasks. In humans and rodents, aberrant touch sensitivity perinatally is predictive of ASD-linked traits later in life. The molecules and mechanisms underlying touch sensation are just being elucidated, and little is known about how they relate to ASD. Touch sensation begins with the activity of mechanically activated PIEZO2 channels that transduce forces into electrical signals. The overall objective of the proposed research is to investigate the role(s) of the Ca2+ sensing protein caldendrin in regulating PIEZO2, touch sensation, and neurodevelopmental processes controlling cognition/affective behaviors. Our project builds on our discovery that mice lacking caldendrin (Cabp1 KO) display tactile hypersensitivity and increased activity of PIEZO2 in dorsal root ganglion neurons (DRGNs). Neurite outgrowth, which depends on PIEZO2 as well as Cav1 L-type Ca2+ channels, is abnormal in Cabp1 KO DRGNs and differs in cultures from males and females. Moreover, Cabp1 KO mice exhibit ASD-like phenotypes, such as anxiety and anti-social behavior, which are more severe in males than females. Considering that genetic silencing of some ASD-related genes in DRGNs of neonatal mice causes tactile hypersensitivity and ASD-linked behaviors in adulthood, our central hypothesis is that caldendrin modulates PIEZO2, Cav1, and the structural maturation of DRGNs early in development, which has sex-specific effects in driving synaptic plasticity in the brain and cognitive, affective, and social behaviors in adulthood. We will use state of the art methods in biochemistry, electrophysiology, and optical imaging to test the following specific aims: (1) elucidate the mechanism whereby caldendrin modulates the activity of PIEZO2; (2) define the contributions of caldendrin to sex- specific patterns of neurite development; and (3) determine how loss of function of caldendrin leads to aberrant cognitive/affective behaviors.