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Selective control of inhibitory synapse development by Slitrk3-PTPδ trans-synaptic interaction

Nature Neuroscience volume 15, pages 389–398 (2012)Cite this article

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Abstract

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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Figure 1: Slitrk3 selectively induces functional inhibitory presynaptic differentiation in co-culture.
Figure 2: Recombinant Slitrk3 localizes to inhibitory postsynaptic sites.
Figure 3: Slitrk3 knockdown decreases the density of inhibitory synapses in hippocampal culture.
Figure 4: Slitrk3−/− mice have reduced inhibitory synapse density in CA1 region of hippocampus.
Figure 5: Slitrk3−/− mice have reduced inhibitory synaptic transmission in CA1 of the hippocampus.
Figure 6: Slitrk3−/− mice exhibit increased seizure susceptibility and abnormal epileptiform activities in EEG recording.
Figure 7: PTPδ is a presynaptic binding partner for Slitrk3.
Figure 8: Slitrk3 requires PTPδ for induction of inhibitory presynaptic differentiation.

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Acknowledgements

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.

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Authors and Affiliations

  1. Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada

    Hideto Takahashi, Tuhina Prasad & Ann Marie Craig

  2. Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI), Wako-shi, Japan

    Kei-ichi Katayama, Yoshifumi Matsumoto, Maya Ota & Jun Aruga

  3. Laboratory for Cortical Circuit Plasticity, RIKEN BSI, Wako-shi, Japan

    Kazuhiro Sohya & Tadaharu Tsumoto

  4. Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama, Japan

    Kazuhiro Sohya & Hiroyuki Miyamoto

  5. Laboratory for Neurobiology of Synapse, RIKEN BSI, Wako-shi, Japan

    Hiroyuki Miyamoto

  6. Education and Research Support Center, Gunma University Graduate School of Medicine, Maebashi, Japan

    Hiroki Yasuda

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Contributions

H.T. performed all of the experiments involving co-culture, neuron culture localization, RNAi knockdown and protein binding assays. K.K. and J.A. performed the mouse gene targeting. K.S. and H.Y. performed the electrophysiological experiments and analysis. H.M. performed the EEG experiments. M.O., T.P. and H.T. performed the mouse immunofluorescence analysis. Y.M. performed the mouse western blot analysis. A.M.C., J.A. and T.T. supervised the project. H.T. and A.M.C. conceived the project and prepared the manuscript with critical input from J.A.

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Correspondence to Jun Aruga or Ann Marie Craig.

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Takahashi, H., Katayama, Ki., 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

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