Mechanism of Par1c-mediated AMPA receptor trafficking and synaptic plasticity

Project Summary/Abstract The human brain is remarkably unique in its high capacity to learn and adapt to new environments, which has been attributed to the plasticity of synaptic connections. One form of synaptic plasticity, long-term potentiation (LTP), is associated with AMPA receptor trafficking to the surface of dynamic postsynaptic protrusions called dendritic spines. GluA2-deficient mice show enhanced LTP, supporting that regulation of synaptic surface GluA2 levels is important for LTP expression. However, the mechanism underlying GluA2 trafficking and how this translates to changes in synaptic plasticity is unclear. We have unexpectedly identified a significant increase in synaptic GluA2 in the hippocampi of forebrain-specific conditional knockout (cKO) of partitioning defective 1c (Par1c), also known as microtubule affinity-regulating kinase 1 (MARK1) mice. In addition, these mice exhibit reduced spine formation and impaired spatial learning. This suggests a potential role for Par1c in synaptic plasticity and cognitive functions through regulation of GluA2 trafficking. Importantly, genetic evidence supports that Par1c functions in higher level cognition. Single nucleotide polymorphisms (SNPs) in MARK1 have been associated with autism spectrum disorder (ASD) and bipolar disorder. Furthermore, MARK1 is highly expressed in forebrain pyramidal neurons and exhibits human-specific accelerated evolution, suggesting its importance in the development of cognition. However, the role of Par1c in AMPA receptor trafficking and synaptic plasticity remains unknown. Considering Par1c cKO mice show a significant increase in synaptic GluA2, we hypothesize that Par1c promotes synaptic plasticity by limiting GluA2 trafficking to the spine surface. When Par1c is knocked out, there will be increased synaptic incorporation of GluA2-containing AMPA receptors, leading to reduced spine density and impaired learning. Interestingly, unbiased phosphoproteomic analysis of Par1c cKO hippocampi revealed 7 of 17 significantly dysregulated proteins are associated with endocytic trafficking. Thus, Aim 1 will test the hypothesis that Par1c regulates GluA2 trafficking through phosphorylation of a potential novel target of Par1c identified through phosphoproteomic screen. Aim 2 will determine if synaptic plasticity induction requires Par1c activation using a novel, synaptic-targeted photoactivatable Par1c. The proposed work will elucidate the role of Par1c in regulating AMPA receptor trafficking and synaptic plasticity. Importantly, this project will train the applicant in multidisciplinary techniques including molecular biology, biochemical assays, FRET and FRAP imaging, primary neuronal cultures, and electrophysiology. It will also provide opportunities for the development of critical thinking, written and oral communication skills, and the execution of rigorous and reproducible science. The thorough mentorship and resources available to the applicant combined with her extensive and interdisciplinary neuroscience background will ensure her development into a successful, independent scientific professional.