Brain Sciences

• This proposal seeks to unravel the molecular basis of neural circuits by elucidating mechanisms of a subset of trans-synaptic adhesion signaling pathways. Specifically, experiments described in the proposal are designed to tackle both canonical and non-canonical roles of synapse organizers in the context of specific neural circuits and to determine whether they specify specific neural circuit properties.
• We will implement a highly interdisciplinary and sophisticated strategy that integrates structural biology, biochemistry, biophysics, high-resolution imaging, mouse genetics, electrophysiology, and behavior.
• Collectively, these approaches will decipher key molecular principles underlying synapse diversity and specificity and enhance our understanding of pathophysiological mechanisms underlying brain disorders associated with impairment of specific neural circuit properties.

Using both mouse and human neurons, and primarily employing loss-of-function analyses targeting the key postsynaptic adhesion molecules, LRRTMs, Slitrks, MDGAs and type II classic cadherins—the major molecular targets in the current proposal—we will address the following four specific aims to elucidate the molecular logic underpinning the constructing of universal neural circuits:

• Aim1 : Identification and validation of synapse-organizing functions of trans-synaptic adhesion proteins
• Aim2 : Determination of the network of trans-synaptic adhesion signaling pathways in synaptic cleft and intracellular regions of pre- and postsynaptic neurons
• Aim3 : Elucidation of the role of trans-synaptic adhesion signaling pathways in controlling input-output relations of neural circuits in a brain region-, cell-type-, and projection-specific manner
• Aim4 : Deconvolution of dissociable neural circuit properties organized by trans-synaptic adhesion signaling pathways that are involved in eliciting specific mouse behavioral abnormalities implicated in certain neurological disorders