Investigating the role of SORBS1 in synaptogenesis

Abstract

Synaptogenesis is an exquisite process in which synaptic contacts establish between neurons. The locations, numbers and types of synapses are under precise regulation during synaptogenesis, to ensure the homeostasis of nervous system is maintained. The molecular mechanisms underlying synapse formation and the specification of synapse diversity is not fully understood. Although some related adhesion molecules and scaffold proteins in synapse have been implicated in synapse formation, the details of their roles in synaptogenesis are still needed to be investigated.

In this study, we identified that SORBS1 specifically localizes with PSD-95 (postsynaptic density protein 95) at excitatory synapses. Knocking down of SORBS1 in neurons impairs spine formation. This defect in spine morphogenesis could be rescued by introducing shRNA-resistant SORBS1, indicating that SORBS1 regulates spine morphogenesis in neurons. Phosphorylation levels of WAVE1 (Wiskott-Aldrich syndrome protein family member 1) and PAK1 (α-p21-activated kinase 1) increase significantly in SORBS1-KD neurons, suggesting that abnormal actin polymerization and depolymerization might contribute to the abnormality in spine morphology. Inhibiting WAVE1 function by targeting it to mitochondria could partially rescue the defects in SORBS1-KD neurons. Taken together, we considered that SORBS1 localizes and functions in excitatory synapses, and could regulate the spine morphology through WAVE1-Arp2/3 pathway.

Date of Award	2018
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology