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.