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

Synaptic excitation and inhibition are two highly coordinated opposing forces in the central nervous system. The equilibrium between these two opposing forces, E/I balance, affects many brain functions, particularly in the mammalian cerebral cortex. Neurotransmitter receptors and cell adhesion molecules are though to have a major role in this process. Previous work from our laboratory identified SorCS1 as a critical regulator of the synaptic abundance of neurotransmitter receptors and cell adhesion molecules. SorCS1 binds the synaptic adhesion molecule neurexin and regulates its surface abundance. Moreover, SorCS1 localizes to endosomal recycling compartments and excitatory synapses. Hence, I hypothesize that SorCS1 binds cargo proteins in recycling endosomes and controls their trafficking to the plasma membrane. This sustains the pool of proteins at the synapse, which is required for proper synaptic function and can adjust synapse strength and number. Synaptic surface receptors and SorCS1 have been linked to synaptopathies, such as autism and schizophrenia, which are also characterized by defects in neurotransmission and E/I imbalance. Here, I will determine how SorCS1 regulates the trafficking of synaptic receptors and elucidate the role of SorCS1 in controlling synaptic function and E/I balance in neural circuits. These experiments will give insight into the underlying mechanisms of synaptopathies, which may ultimately allow the design of therapeutic interventions.