NCK1 FUNCTIONS IN THE BRAIN TO REGULATE DENDRITIC SPINE FORMATION, COGNITION, AND BEHAVIOUR

Abstract

NCK1, encodes for the non-catalytic region of tyrosine kinase adaptor protein (NCK1). NCK1 has previously been shown to modulate cellular actin, although its role in CNS development and function remain unknown. Here, I examined neurodevelopmental and behavioural defects using a murine model in which NCK1 was inactivated. I show that NCK1 is ubiquitously expressed in neurons throughout the brain but does not grossly affect neuronal development. However, loss of NCK1 leads to defects in memory, learning, and in anxiety-like behaviours. Examination of the hippocampal region revealed that NCK1 is necessary for normal synaptic density, and morphology of the postsynaptic density. Mechanistically, NCK1 affects synaptic structures by regulating the rate of actin turnover and polymerization, suggesting that NCK1 functions intrinsically in neurons to stabilize actin dynamics and promote synaptic integrity. In addition to memory defects, mice lacking NCK1 show context dependent defects in anxiety-like and stress hormone responses. These defects are ameliorated with treatment with Diazepam. The anxiety-like defects is linked with a loss of synaptic density in the basal lateral amygdala (BLA) and decreased neuronal activation in the prefrontal cortex and in inhibitory interneurons of the BLA, implicating NCK1 in inhibitory control of circuits important for regulating anxietylike behaviours. Combined, my work suggests that NCK1 functions in the CNS to stabilize synaptic actin dynamics necessary for the development of neuronal circuits important for learning, memory and anxiety-like behaviours.