Novel role of mitotic kinesin KIF11 in structural plasticity and memory

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Project Summary Mitotic cells dynamically regulate microtubule (MT) architecture through the use of the MT motors: kinesin and dynein. Intriguingly, many of the canonical mitotic kinesins are expressed in post-mitotic neurons. These kinesins are thought to participate in repositioning MTs in neurons, yet their precise function and how they are regulated in neurons are unknown. Notably, mutations in kinesin-5 result in disorders associated with intellectual disabilities in humans, however, there is a lack of mechanistic understanding of why this occurs. Previously, the Puthanveettil lab revealed that members of the kinesin family of proteins (KIFs) are physiologically regulated in neurons and are required for long-term memory storage. Recent studies from the lab uncovered that KIF11 (Kinesin-5), acts as an inhibitory constraint on excitatory synaptic transmission in hippocampal neurons. RNAi- mediated loss-of-function analysis of KIF11 resulted in increased mini excitatory post-synaptic currents frequencies, increased dendritic branching, and increased synapse density. KIF11 is the only known homotetrameric kinesin, with four, slow motor domains that face outward to bind interpolar MTs during mitosis, and brake against other kinesins to ensure proper spindle formation. It is unknown how KIF11 mediates structural changes in hippocampal neurons, and whether KIF11 has a role in long-term memory storage. My central hypothesis is that KIF11 mediated regulation of MT dynamics is required for the activity-dependent structural changes in dendritic spines and long-term memory. To test this, in Aim1 I will uncover the mechanism behind how KIF11 regulates structural plasticity through examining activity-dependent changes in spine morphology following glutamate uncaging in WT, KIF11 KD, and KIF11 overexpression neurons by two-photon microscopy (2P) imaging while simultaneously visualizing MT dynamics via EB1. In Aim 2 I will test the effects of the loss of function and gain of function of KIF11 in dorsal CA1 neurons in learning and memory behavior assays. Completion of these aims will bring novel insights into the mechanism and regulation of KIF11 in structural plasticity and memory. Moreover, these studies will significantly advance our understanding of mitotic kinesins in post-mitotic neurons.