A trans-synaptic mechanism for the development and function of a neural circuit
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Date
2020
Authors
Silwal, Prabhisha
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Abstract
Synapses are formed by high affinity trans-synaptic interactions between pre- and post- synaptic proteins. Any disturbance in these interactions may affect synaptogenesis. We assessed the consequences of disrupted trans-synaptic interaction between presynaptic neurexins and postsynaptic LRRTM4 proteins in vivo. We found that neurexins bind to LRRTM4 only in the presence of heparan sulfate (HS) chains. When HS binding site on LRRTM4 was mutated, they could not bind to neurexins. Analysis of brain collected from the knock-in mice with mutation in the functional HS binding domain of LRRTM4 showed reduction in excitatory synapses at dentate gyrus (DG). The binding of neurexins and LRRTM4 via HS chains recruited PTPσ to induce optimal presynaptic differentiation. The knock-in mice also revealed reduced levels of PTPσ and neurexins in the dentate gyrus lysates. Therefore, our results provide evidence that trans-synaptic interactions between neurexins and LRRTM4 via HS chains are required for excitatory synapse formation in the DG; and any disruption in their interaction impair excitatory synapse formation and development.
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Keywords
Synapse, neurexins, LRRTMs, cell adhesion molecules
Citation
Roppongi, R.T., Dhume, S., Padmanabhan, N., Silwal, P., Zahra, N., Karimi, B., Bomkamp, C., Patil, C., Champagne-Jorgensen, K., Twilley, R.E., Zhang, P., Craig, A.M., Jackson, M.F., Siddiqui, T.J. (2020). LRRTMs organize synapses through differential engagement of neurexin and PTPσ. Neuron (in Press)