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

Abstract

Balanced development of excitatory and inhibitory synapses is required for normal brain function, and their imbalance may underlie pathogenesis of neuropsychiatric disorders. Compared with many identified trans-synaptic adhesion complexes that organize excitatory synapses, little is known about organizers specific for inhibitory synapses. Here we report Slit and NTRK-like family member 3 (Slitrk3) as a postsynaptic adhesion molecule that selectively regulates inhibitory synapse development via trans-interaction with axonal tyrosine phosphatase receptor PTPδ. Slitrk3 expressed in fibroblasts triggers only inhibitory presynaptic differentiation in contacting axons of cocultured rat hippocampal neurons. Recombinant Slitrk3 preferentially localizes to inhibitory postsynaptic sites. Slitrk3-deficient mice exhibit decreases in inhibitory but not excitatory synapse number and function in hippocampal CA1 neurons and exhibit increased seizure susceptibility and spontaneous epileptiform activity. Slitrk3 requires trans-interaction with axonal PTPδ to induce inhibitory presynaptic differentiation. These results identify Slitrk3-PTPδ as an inhibitory-specific trans-synaptic organizing complex required for normal functional GABAergic synapse development.

The Leucine-Rich Repeat Superfamily of Synaptic Adhesion Molecules: LRRTMs and Slitrks

“…A recent expression screen for synaptogenic proteins uncovered several LRR proteins that have synaptogenic activities (Linhoff et al, 2009). One synaptogenic protein identified in this study was Slitrk2, which was shown to induce both excitatory and inhibitory presynaptic differentiation (Linhoff et al, 2009;Takahashi et al, 2012). Taken together, these observations indicate that a subset of Slitrks function in promoting synapse formation and maturation.…”

“…Other Slitrks induce both excitatory and inhibitory synapse differentiation. Slitrk3-deficient mice exhibit a specific decrease in inhibitory synapse number and function and an increase in seizure susceptibility (Takahashi et al, 2012). The authors of this latter study demonstrated that all six Slitrks mediate trans-interaction with receptor protein tyrosine phosphatase-δ (PTPδ), an action that is responsible for the inhibitory-specific synaptogenic activities of Slitrks, at least, in artificial synapse formation assays.…”

“…Knockout mice have also been used recently to demonstrate the involvement of Slitrk3 and -5 in synapse formation (Shmelkov et al, 2010;Takahashi et al, 2012). In cultured neurons, Slitrk5 localizes to postsynaptic sites.…”

“…Inhibitory synapse formation (Slitrk3) (Takahashi et al, 2012) TrkC PTPσ (in vitro) Excitatory synapse formation (Takahashi et al, 2011…”

“…presynaptic differentiation in artificial synapse formation assays (Takahashi et al, 2012). Other Slitrks induce both excitatory and inhibitory synapse differentiation.…”