Ndel1 is a microtubule-associated protein (MAP) widely recognized as an integrator of the cytoskeleton. In the developing brain, Ndel1 impacts neurogenesis, nucleokinesis and neuronal migration through interactions with its binding partners, Lis1 and Dynein. Ndel1 knockout mice are embryonic lethal; therefore, the Nguyen lab created conditional knockout mice for Ndel1 (Ndel1 CKO) in CA1 hippocampal excitatory neurons 1 month post birth, to investigate its roles in the postnatal brain. It has been shown that Ndel1 CKO animals exhibit microtubule (MT) fragmentation in CA1 pyramidal neurons associated with synaptic and dendritic pathology, as well as spatial memory impairment. Additionally, Reelin, a secreted glycoprotein involved in the MTs regulation, synaptic plasticity and cell positioning, is reduced in the hippocampus of Ndle1 CKO mice. Interestingly, a single injection of Reelin reduces the MT fragmentation in CA1 pyramidal neurons as well as the synaptic/dendritic pathology.
My thesis investigates the significance of Ndel1 and Reelin in postnatal hippocampal integrity and how it impacts spatial learning and memory. My work shows that cellular/anatomical defects do not lead to cell death in the hippocampus of mutant mice. Additionally, CA1 pyramidal neurons become dispersed postnatally, which is decreased with Reelin supplementation. I found an upregulation of Lis1 in Ndel1 CKO hippocampi. As overexpression of Lis1 in the brief presence of nocodazole (MT destabilization agent) generates fragments of MTs disconnected from the centrosomes (Smith et al, Nat Cell Biol 2000), I reasoned that the MTs fragmentation in CA1 pyramidal neurons of Ndel1 CKO mice involves increased Lis1 dosage. Finally, I found that a single injection of Reelin improves the spatial memory of Ndel1 CKO mice during the Morris Water Task. My work provides insight into the postnatal roles of Ndel1 and Reelin in CA1 integrity and how that ultimately impacts spatial learning and memory in Ndel1 CKO mice.