A combinatorial code of neurexin-3 alternative splicing controls inhibitory synapses via a trans-synaptic dystroglycan signaling loop

Justin H. Trotter (), Cosmos Yuqi Wang, Peng Zhou, George Nakahara and Thomas C. Südhof ()
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Justin H. Trotter: Stanford University School of Medicine
Cosmos Yuqi Wang: Stanford University School of Medicine
Peng Zhou: Stanford University School of Medicine
George Nakahara: Stanford University School of Medicine
Thomas C. Südhof: Stanford University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: Abstract Disrupted synaptic inhibition is implicated in neuropsychiatric disorders, yet the molecular mechanisms that shape and sustain inhibitory synapses are poorly understood. Here, we show through rescue experiments performed using Neurexin-3 conditional knockout mice that alternative splicing at SS2 and SS4 regulates the release probability, but not the number, of inhibitory synapses in the olfactory bulb and prefrontal cortex independent of sex. Neurexin-3 splice variants that mediate Neurexin-3 binding to dystroglycan enable inhibitory synapse function, whereas splice variants that don’t allow dystroglycan binding do not. Furthermore, a minimal Neurexin-3 protein that binds to dystroglycan fully sustains inhibitory synaptic function, indicating that trans-synaptic dystroglycan binding is necessary and sufficient for Neurexin-3 function in inhibitory synaptic transmission. Thus, Neurexin-3 enables a normal release probability at inhibitory synapses via a trans-synaptic feedback signaling loop consisting of presynaptic Neurexin-3 and postsynaptic dystroglycan.

Date: 2023
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DOI: 10.1038/s41467-023-36872-8

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