Abstract
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 formation and function, as well as learning and memory. Here, we focused on the importance of the actin regulator, non-catalytic region of tyrosine kinase adaptor protein 1 (NCK1), in hippocampal dependent behaviours 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 post-mitotic neurons but is dispensable for neuronal proliferation and migration in the developing hippocampus. Morphologically, NCK1 is not necessary for overall neuronal dendrite development. However, neurons lacking NCK1 have lower dendritic spine and synapse densities in vitro and in vivo. EM analysis reveal increased 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 spine formation.
SIGNIFICANCE STATEMENT:
Understanding the molecular signaling pathways that contribute to memory formation, maintenance, and elimination will lead to a better understanding of the genetic influences on cognition and cognitive disorders and will direct future therapeutics. Here, we report that the NCK1 adaptor protein modulates actin-filament turnover in hippocampal dendritic spines. Mice lacking NCK1 show sex-dependent deficits in hippocampal memory formation tasks, have altered postsynaptic densities, and reduced synaptic density. Together, our work implicates NCK1 in the regulation of actin cytoskeleton dynamics and normal synapse development which is essential for memory formation.
Footnotes
The authors declare no competing financial interests
This work was supported by funding from the Canadian Institutes of Health Research (MOP-84366, 79413 and PJT-159738) to JPF, and NSERC Discovery grants (RGPIN/005562-2018 and RGPIN 326821 to BK and SRK. We thank Mary Ann Trevors, facility manager of the electron microscope facility at Dalhousie University, for technical support and specimen preparation for the transmission electron microscope.
