Exploring the role of Neuroligin-1 in synapse formation and function

Controlling the precise balance between excitation and inhibition (E/I balance) is critical for information processing in the brain.

This equilibrium is regulated at the level of individual synapses, which can be either excitatory or inhibitory depending of the type of neurotransmitter released.

It is well established that cell adhesion molecules such as neurexins (NRXs) and neuroligins (NLs) play important roles in synapse formation and specification.

In humans, several genetic mutations in NLs are associated with Autism Spectrum Disorders (ASD) but how those mutations act in the establishment of those disorders remains unclear.

One hypothesis is that mutations found in ASD patients can affect the interactions of NLs to specific protein binding partners and/or alter signaling pathways, which could contribute to disrupt the E/I balance.

Interestingly, the host group recently discovered a molecular mechanism in which the phosphorylation of unique tyrosine residue located in the intracellular domain of NL1 regulates the differential assembly of excitatory versus inhibitory synapses.

Furthermore, in the absence of highly specific antibodies compatible with immunostaining of native adhesion molecules, little is known about the precise distribution of endogenous NL1 within the synapse.

In this project we will #1) decipher the localization of endogenous NL1 and its modulation between excitatory and inhibitory synapses based on its phosphorylation state by using a new transgenic knock-in mouse line in which endogenous NL1 has been tagged with a small biotin acceptor peptide (BAP-NL1); #2) we will uncover how ASD-linked mutations in NL1 affect synaptic changes at the morphological and functional levels, in both physiological and ASD conditions.

ExploNL1 will shed light on the basic molecular mechanisms regulating the differentiation of excitatory and inhibitory synapses, and as a consequence the underlying pathological basis of ASDs.