Sanil Sansar Abstract
Abstract: Formation of synaptic connections in the nervous system must be tightly regulated to ensure that the nervous system develops with the correct number and proportion of excitatory and inhibitory synapses. Failure to do so may result in aberrant nervous system formation, leading to dysfunction in control of sensory/motor, cognitive, emotional, and social function. Autism Spectrum Disorders (ASDs) occur with an imbalance in the formation of excitatory and inhibitory synapses. ASDs are prevalent multifactorial neurodevelopmental disorders, affecting 1 in 68 children (1 in 42 boys and 1 in 189 girls) in the United States. These children have deficiencies in social skills and verbal communication and by repetitive behavioral patterns. The number and proportion of excitatory and inhibitory synapses require that specific synaptic cell adhesion proteins, including neurexin (NRX), be transported in the anterograde direction to developing presynaptic terminals. Here, NRX is inserted into the presynaptic membrane and interact with their binding partners, neuroligins, which inserted into the post-synaptic membrane. Studies in B35 neuroblastoma cells are consistent with the idea that NRXs are transported in vesicles. Since NRX distribution is disrupted in ASD, we hypothesized that vesicle-localized NRXs are transported by cellular anterograde transporter motors, kinesins, in a process regulated by small guanosine nucleotide triphosphatases (GTPases) of the Rab and Rho subfamilies. We have tested our hypothesis in rat primary cortical neurons and the Caenorhabditis elegans animal model. We systematically screened for kinesin motor proteins and Rab and Rho GTPases and found that the process of vesicular transport of NRX-1 is carried out by a kinesin that contains light chain-2 and kinesin like protein-6. This process is regulated by RAB-8, 37, 3, 6.1, 27, 10 and CED-10, a homolog of RAC1. Collectively, we interpret these data to suggest a model in which vesicular NRX is transported between cellular compartments and to the cell membrane by kinesin motors, a process regulated by small GTPases. These findings will contribute to explaining the pathogenesis of neuropsychiatric disorders like autism that involve improper transport of synaptic proteins like NRX by defining the mechanisms of NRX delivery to presynaptic terminals.
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