Balanced development of excitatory and inhibitory synapses is required for normal brain function, and an imbalance in this development may underlie the pathogenesis of many neuropsychiatric disorders. Compared with the many identified trans-synaptic adhesion complexes that organize excitatory synapses, little is known about the organizers that are specific for inhibitory synapses. We found that Slit and NTRK-like family member 3 (Slitrk3) actS as a postsynaptic adhesion molecule that selectively regulates inhibitory synapse development via trans-interaction with axonal tyrosine phosphatase receptor PTPδ. When expressed in fibroblasts, Slitrk3 triggered only inhibitory presynaptic differentiation in contacting axons of co-cultured rat hippocampal neurons. Recombinant Slitrk3 preferentially localized to inhibitory postsynaptic sites. Slitrk3-deficient mice exhibited decreases in inhibitory, but not excitatory, synapse number and function in hippocampal CA1 neurons and exhibited increased seizure susceptibility and spontaneous epileptiform activity. Slitrk3 required trans-interaction with axonal PTPδ to induce inhibitory presynaptic differentiation. These results identify Slitrk3-PTPδ as an inhibitory-specific trans-synaptic organizing complex that is required for normal functional GABAergic synapse development.
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We thank X. Zhou (Brain Research Centre, University of British Columbia) for excellent preparation of neuron cultures, N. Takashima (Lab for Behavioral and Developmental Disorders, RIKEN BSI) for technical assistance with seizure experiments and C. Nishioka (Research Resource Center, RIKEN BSI) for help generating Slitrk3 knockout mice. This work was supported by a NeuroDevNet Canadian Network of Centre of Excellence Opportunities Initiative Award, US National Institutes of Health grant MH070860, Canadian Institutes of Health Research grant MOP-84241and Canada Research Chair awards to A.M.C., a Japan Society for the Promotion of Science Postdoctoral Fellowship for Research Abroad and a National Alliance for Research on Schizophrenia and Depression (Brain and Behavior Research Fund) Young Investigator grant to H.T., and RIKEN BSI funds and a Ministry of Education, Culture, Sports, Science (Japan) Grant-in-Aid for Scientific Research (A) (21240031) to J.A.
The authors declare no competing financial interests.
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Takahashi, H., Katayama, K., Sohya, K. et al. Selective control of inhibitory synapse development by Slitrk3-PTPδ trans-synaptic interaction. Nat Neurosci 15, 389–398 (2012). https://doi.org/10.1038/nn.3040