PT  - JOURNAL ARTICLE
AU  - Stokes, Eric G.
AU  - Kim, Hyeonho
AU  - Ko, Jaewon
AU  - Aoto, Jason
TI  - A Systematic Structure-Function Characterization of a Human Mutation in Neurexin-3α Reveals an Extracellular Modulatory Sequence That Stabilizes Neuroligin-1 Binding to Enhance the Postsynaptic Properties of Excitatory Synapses
AID  - 10.1523/JNEUROSCI.1847-23.2024
DP  - 2024 Oct 09
TA  - The Journal of Neuroscience
PG  - e1847232024
VI  - 44
IP  - 41
4099  - http://www.jneurosci.org/content/44/41/e1847232024.short
4100  - http://www.jneurosci.org/content/44/41/e1847232024.full
SO  - J. Neurosci.2024 Oct 09; 44
AB  - α-Neurexins are essential and highly expressed presynaptic cell-adhesion molecules that are frequently linked to neuropsychiatric and neurodevelopmental disorders. Despite their importance, how the elaborate extracellular sequences of α-neurexins contribute to synapse function is poorly understood. We recently characterized the presynaptic gain-of-function phenotype caused by a missense mutation in an evolutionarily conserved extracellular sequence of neurexin-3α (A687T) that we identified in a patient diagnosed with profound intellectual disability and epilepsy. The striking A687T gain-of-function mutation on neurexin-3α prompted us to systematically test using mutants whether the presynaptic gain-of-function phenotype is a consequence of the addition of side-chain bulk (i.e., A687V) or polar/hydrophilic properties (i.e., A687S). We used multidisciplinary approaches in mixed-sex primary hippocampal cultures to assess the impact of the neurexin-3αA687 residue on synapse morphology, function and ligand binding. Unexpectedly, neither A687V nor A687S recapitulated the neurexin-3α A687T phenotype. Instead, distinct from A687T, molecular replacement with A687S significantly enhanced postsynaptic properties exclusively at excitatory synapses and selectively increased binding to neuroligin-1 and neuroligin-3 without changing binding to neuroligin-2 or LRRTM2. Importantly, we provide the first experimental evidence supporting the notion that the position A687 of neurexin-3α and the N-terminal sequences of neuroligins may contribute to the stability of α-neurexin–neuroligin-1 trans-synaptic interactions and that these interactions may specifically regulate the postsynaptic strength of excitatory synapses.