Abstract
Synapse formation and regulation require signaling interactions between pre- and postsynaptic proteins, notably cell adhesion molecules (CAMs). It has been proposed that the functions of neuroligins (Nlgns), postsynaptic CAMs, rely on the formation of trans-synaptic complexes with neurexins (Nrxns), presynaptic CAMs. Nlgn3 is a unique Nlgn isoform that localizes at both excitatory and inhibitory synapses. However, Nlgn3 function mediated via Nrxn interactions is unknown. Here we demonstrate that Nlgn3 localizes at postsynaptic sites apposing vesicular glutamate transporter 3-expressing (VGT3+) inhibitory terminals and regulates VGT3+ inhibitory interneuron-mediated synaptic transmission in mouse organotypic slice cultures. Gene expression analysis of interneurons revealed that the αNrxn1+AS4 splice isoform is highly expressed in VGT3+ interneurons as compared with other interneurons. Most importantly, postsynaptic Nlgn3 requires presynaptic αNrxn1+AS4 expressed in VGT3+ interneurons to regulate inhibitory synaptic transmission. Our results indicate that specific Nlgn-Nrxn signaling generates distinct functional properties at synapses.
Highlights
In central synapses, cell adhesion molecules (CAMs) are major players in trans-synaptic interactions (de Wit and Ghosh, 2016) that serve a primary role in initiating synapse formation by directing contact between axonal and dendritic membranes
We recently found that Nlgn3D, which lacks both of the A1 and A2 alternative splice insertions, is the major Nlgn3 splice isoform expressed in hippocampal CA1 pyramidal neurons and regulates both excitatory and inhibitory synaptic transmission (Uchigashima et al, 2020)
Nlgn3 is enriched at VGT3+ GABAergic synapses in the hippocampal CA1 region
Summary
Cell adhesion molecules (CAMs) are major players in trans-synaptic interactions (de Wit and Ghosh, 2016) that serve a primary role in initiating synapse formation by directing contact between axonal and dendritic membranes. Emerging evidence suggests that trans-synaptic interactions are important for synapse identity, function, plasticity, and maintenance (Biederer et al, 2017; Campbell and Tyagarajan, 2019; Sudhof, 2017). Neuroscience exist due to large gene families and alternative splicing, generating a vast array of possible combinations of pre- and postsynaptic CAMs. some specific trans-synaptic interactions of CAMs have been reported to underlie distinct synaptic properties (Chih et al, 2006; Fossati et al, 2019; Futai et al, 2013), elucidating synaptic CAM complexes that dictate synapse identity and function remains a major challenge
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