The role of Par1c/MARK1 in dendritic spine morphogenesis, plasticity, and cognitive functions in mice
Creators: name: Kelly-Castro, Emily C.
Publisher: name: No Publisher Supplied
Year: 2022

description: Dendritic spines are dynamic postsynaptic structures that play an essential role in cognitive functions, such as learning and memory. The dysregulation of spine size, shape, and density may lead to learning and memory deficiencies and neurological disorders such as autism spectrum disorders (ASD). Previous studies from our laboratory have demonstrated that partitioning defective 1 c (Par1c), also known as microtubule affinity regulating kinase 1 (MARK1), regulates dendritic spine morphogenesis and plasticity in cultured hippocampal neurons. Interestingly, studies have found multiple single nucleotide polymorphisms (SNPs) of MARK1 associated with ASD and bipolar disorder. However, the role of Par1c/MARK1 in synaptic plasticity and cognitive functions in vivo is still unknown.Therefore, we developed a conditional knockout (cKO) MARK1 mouse model to examine the effects of MARK1 depletion on spine morphogenesis and cognitive functions such as learning and memory. In this mouse model, MARK1 is depleted postnatally from pyramidal neurons of the forebrain, including the hippocampus and the cerebral cortex. After successfully developing the Par1c/MARK1 conditional KO mice, we evaluated the effects of depleting Par1c/MARK1 on spine morphogenesis and plasticity. We use the Golgi Staining Technique, where results show a significant decrease in dendritic spine density and spine length while there is an increase in the width of the spine head and neck. The Par1c/MARK1 cKO mice also show an increase in stubby spines. Hence the Par1c/MARK1 cKO mice are showing fewer, shorter and wider spines on the CA1 apical dendrites when compared to the control. Furthermore, we conducted a battery of behavioral experiments to evaluate the effects due to the loss of Par1c/MARK1. The Par1c/MARK1 cKO mice showed a spatial learning defect in the Morris Water Maze test and significantly reduced anxiety-like behavior in the elevated plus-maze. However, spatial memory, working memory, sociability, and general activity levels appear to be expected in these mice.Further on, we evaluated the effects of loss of Par1c/MARK1 over the relative mean protein expression in crude synaptosomes. We found increased protein expression of GKAP and GluR2 in the Par1c/MARK1 cKO mice. Lysate hippocampal tissue of the Par1c/MARK1 cKO was sent to the Rutgers Proteomics Center--Mass Spectrometry Facility to conduct a phosphoproteomic analysis. Results show that Par1c/MARK1 targets synaptic proteins and proteins regulating cytoskeletal dynamics and vesicle trafficking. Specifically, there is a significant decrease in phosphorylation at residue S843 of RalGAPα1, a GTPase-activating protein (GAP) for Ral GTPases. Our studies point to an essential role for Par1c/MARK1 in regulating dendritic spine morphogenesis, spatial learning, and anxiety-related behavior in vivo. Par1c/MARK1 might also play a role in lipid raft dynamics and GluR2 receptor trafficking. Since Ral GTPases regulate membrane trafficking, future studies will examine whether Par1c/MARK1 regulates receptor trafficking through RalGAPα1.