Our long term goal is to understand how chemical synapses in the brain develop and are modified by experience for higher brain functions such as learning, memory and cognition.
Novel trans-synaptic mechanisms of synapse developmentThe major objective of our laboratory is to understand how excitatory and inhibitory synapses develop with a proper balance for the normal functions of neural networks and how an imbalance in their development is involved in the etiology of neuropsychiatric disorders such as autism spectrum disorders and schizophrenia. We previously carried out unique functional screens to identify synapse-promoting genes (synaptic organizers) and their receptors. Using this approach, we identified and characterized two novel synaptic organizing complexes, TrkC-PTPσ and Slitrk3-PTPδ, which are specific for the development of excitatory and inhibitory synapse, respectively. Yet, we still have very limited evidence about trans-synaptic mechanisms for inhibitory synapse development in spite of GABAergic interneuron diversity and subcellular-specific inhibitory synaptic innervations. Notably, we identified another synapse-promoting gene, the function of which is yet completely uncharacterized. Interestingly, our preliminary data suggest that this gene is selectively involved in inhibitory synapse development. Using comprehensive approaches including molecular and cellular biology, biochemistry, proteomics and genetics, we intend to characterize the function of this novel gene and its encoded protein and to identify its receptor. These studies will contribute to our greater understanding of molecular mechanisms of inhibitory synapse development and its dysfunction in neuropsychiatric disorders.
Modulatory mechanisms of synaptic organizing complexesMany synaptic organizers bind to not only a presynaptic binding partner but also extracellular soluble proteins and/or matrixes, suggesting that those extracellular soluble molecules would modulate synaptic organizer functions. Given that pharmacological manipulations of glutamatergic synapse functions ameliorate the dysfunctions of some mouse models of autism, we will here focus on studying modulatory mechanisms of an excitatory synapse-specific synaptic organizing complex TrkC-PTPσ. We demonstrated that TrkC interacts with PTPσ and neurotrophin-3 (NT-3) via distinct extracellular domains. In general, NT-3 treatment is found to facilitate excitatory synaptic transmission. Further, it has been known that PTPσ binds to chondroitin and heparin sulfate proteoglycans, involved in axon outgrowth and axon guidance. Based on these evidences, we hypothesize that NT-3 and proteoglycans could modulate synapse-organizing functions of the TrkC-PTPσ complex for higher brain functions. These studies may help us define novel molecular basis on synaptic plasticity and also develop a novel therapeutic strategy for cognitive dysfunction.