Role of the sorting receptor SorCS1 in controlling excitation/inhibition balance in neural circuits.

Controlling the precise balance between excitation and inhibition (E/I balance) is critical for information processing in the brain. A perturbed E/I balance has been implicated in the etiology of a wide range of neuropsychiatric disorders. The factors that dictate the balance between excitatory and inhibitory synaptic transmission are still poorly defined, but trans-synaptic interactions between adhesion molecules such as neurexins and neuroligins are thought to be important. The host laboratory recently identified the sorting receptor SorCS1 as a key regulator of the synaptic abundance of glutamate receptors and adhesion molecules, including neurexins and neuroligins. SorCS1 has been associated with a variety of neural disorders, including autism, schizophrenia, and Alzheimer’s disease. I hypothesize that SorCS1 controls E/I balance in the brain by regulating the synaptic abundance of cell surface receptors. I shall test this hypothesis via the following specific aims: Aim 1: To analyse whether SorCS1 regulates synaptic trafficking of adhesion molecules and neurotransmitter receptors under basal conditions and during synaptic activity. Aim 2: To define how SorCS1 affects excitatory and inhibitory synapse function in vitro and in vivo. Aim 3: To determine whether perturbed SorCS1 levels and disease-associated SorCS1 mutations affect E/I balance in neural circuits.