Brain function requires the proper balance between excitatory and inhibitory neurotransmission. Neuronal cells communicate at specialized sites called synapses, which are uniquely outfitted depending on whether they mediate excitatory or inhibitory signals. The process by which synapses develop and are specified as either excitatory or inhibitory still remains to be fully understood. Neuroligins (NLs) are postsynaptic cell adhesio molecules involved in synapse development and function. They have a strong genetic link to autism spectrum disorders, and have been implicated in regulation of the balance between neuronal excitation and inhibition. One NL isoform, NL-2, is located and specifically functions at inhibitory synapses, whereas other NL isoforms function only at excitatory synapses or can act at both types. Because the NL sequences are highly conserved, it is unclear how this specificity occurs. The goal of the proposed work is to elucidate the mechanisms mediating NL-2's location and function specifically at inhibitory synapses. This will be achieved through identification, careful analysis, and characterization of NL-2 postsynaptic signaling and protein interactions at inhibitory synapses.
Specific Aim 1 is to examine phosphorylation, a posttranslational modification of NL-2 by identifying, characterizing, and studying the regulation of these events.
Specific Aim 2 is to characterize the physical and functional interaction of NL-2 with inhibitory specific synaptic scaffold molecules including collybistin. The proposed research will provide insight into the differential ability of NLs to function at distinct types of synapses. It is imporant to understand disease related molecules in the context of normal synapse function. This research can also shed light on larger issues related to synaptic dysfunction in autism spectrum disorders, and how balance between excitation and inhibition is achieved in the brain.
Autism spectrum disorders (ASDs) are a highly heritable group of neurodevelopmental disorders that affect approximately 1% of the population. Probing the genetic basis of autism has revealed that many mutations in genes associated with it are related to synaptic structure and function. Neuroligins are postsynaptic adhesion molecules that have a strong genetic link to autism. Studying their differential roles in excitatory versus inhibitory synapse development will greatly inform our understanding of normal synaptic function, and will likely provide insights into synaptic dysfunction relevant to ASDs.
