NCK1 Modulates Neuronal Actin Dynamics and Promotes Dendritic Spine, Synapse, and Memory Formation

Memory formation and maintenance is a dynamic process involving the modulation of the actin cytoskeleton at synapses. Understanding the signaling pathways that contribute to actin modulation is important for our understanding of synapse for-mation and function, as well as learning and memory. Here, we focused on the importance of the actin regulator, noncata-lytic region of tyrosine kinase adaptor protein 1 (NCK1), in hippocampal dependent behaviors and development. We report that male mice lacking NCK1 have impairments in both short-term and working memory, as well as spatial learning. Additionally, we report sex differences in memory impairment showing that female mice deficient in NCK1 fail at reversal learning in a spatial learning task. We find that NCK1 is expressed in postmitotic neurons but is dispensable for neuronal proliferation and migration in the developing hippocampus. Morphologically, NCK1 is not necessary for overall neuronal den-drite development. However, neurons lacking NCK1 have lower dendritic spine and synapse densities in vitro and in vivo. EM analysis reveal increased postsynaptic density (PSD) thickness in the hippocampal CA1 region of NCK1-deficient mice. Mechanistically, we find the turnover of actin-filaments in dendritic spines is accelerated in neurons that lack NCK1. Together, these findings suggest that NCK1 contributes to hippocampal-dependent memory by stabilizing actin dynamics and dendritic formation.

Automated summary

This study reveals that male mice lacking NCK1 have impairments in short-term and working memory, as well as spatial learning. Additionally, female mice deficient in NCK1 show memory impairment in reversal learning. NCK1 contributes to hippocampal-dependent memory by stabilizing actin dynamics and dendritic formation.