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AMPA- and NMDA-type glutamate receptors mediate distinct postsynaptic signals that differ characteristically among synapses. How postsynaptic AMPA- and NMDA-receptor levels are regulated, however, remains unclear. Using newly generated conditional knockin mice that enable genetic control of neurexin alternative splicing, we show that in hippocampal synapses, alternative splicing of presynaptic neurexin-1 at splice site 4 (SS4) dramatically enhanced postsynaptic NMDA-receptor-mediated, but not AMPA-receptor-mediated, synaptic responses without altering synapse density. In contrast, alternative splicing of neurexin-3 at SS4 suppressed AMPA-receptor-mediated, but not NMDA-receptor-mediated, synaptic responses, while alternative splicing of neurexin-2 at SS4 had no effect on NMDA- or AMPA-receptor-mediated responses. Presynaptic overexpression of the neurexin-1β and neurexin-3β SS4+ splice variants, but not of their SS4− splice variants, replicated the respective SS4+ knockin phenotypes. Thus, different neurexins perform distinct nonoverlapping functions at hippocampal synapses that are independently regulated by alternative splicing. These functions transsynaptically control NMDA and AMPA receptors, thereby mediating presynaptic control of postsynaptic responses. • Neurexin-1 and 3 alternative splicing at SS4 controls distinct synapse properties • Neurexin-1 with an insert in SS4 enhances NMDA-, but not AMPA-receptor, responses • Neurexin-3 with an insert in SS4 suppresses AMPA-, but not NMDA-receptor, responses • Alternative splicing of neurexins thus regulates postsynaptic receptor responses Alternative splicing of presynaptic neurexin-1 and -3 at splice site 4 is shown to regulate the receptor composition of excitatory synapses. Neurexin-1-SS4+ increases NMDA receptor responses, whereas neurexin-3-SS4+ suppresses AMPA receptor responses. Thus, presynaptic neurexin alternative splicing shapes the postsynaptic glutamate receptor composition. [ABSTRACT FROM AUTHOR]

Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with JAK1 gain-of-function (GoF) variants develop atopic dermatitis (AD) and asthma. To explore tissue-specific functions, we inserted a human JAK1 GoF variant (JAK1 GoF ) into mice and observed the development of spontaneous AD-like skin disease but unexpected resistance to lung inflammation when JAK1 GoF expression was restricted to the stroma. We identified a previously unrecognized role for JAK1 in vagal sensory neurons in suppressing airway inflammation. Additionally, expression of Calcb/CGRPβ was dependent on JAK1 in the vagus nerve, and CGRPβ suppressed group 2 innate lymphoid cell function and allergic airway inflammation. Our findings reveal evolutionarily conserved but distinct functions of JAK1 in sensory neurons across tissues. This biology raises the possibility that therapeutic JAK inhibitors may be further optimized for tissue-specific efficacy to enhance precision medicine in the future., Competing Interests: Declaration of interests B.S.K. is founder of KliRNA Biotech; he has served as a consultant for 23andMe, ABRAX Japan, AbbVie, Almirall, Amgen, Arcutis Biotherapeutics, Arena Pharmaceuticals, argenx, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Cara Therapeutics, Clexio Biosciences, Eli Lilly and Company, Escient Pharmaceuticals, Evommune, Galderma, Genentech, GlaxoSmithKline, Granular Therapeutics, Incyte Corporation, Innovaderm Research, Janssen, Kiniksa, LEO Pharma, Maruho, Novartis, Pfizer, Recens Medical, Regeneron Pharmaceuticals, Sanofi, Septerna, Triveni Bio, Vial, and WebMD; he has stock in ABRAX Japan, KliRNA Biotech, Locus Biosciences, and Recens Medical; he holds a patent for the use of JAK1 inhibitors for chronic pruritus; and he has a patent pending for the use of JAK inhibitors for interstitial cystitis. D.A. has contributed to scientific advisory boards at Pfizer, Takeda, FARE, and the KRF. D.B. is the founder of Lab11 Therapeutics.., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Neuromodulators bind to pre- and postsynaptic G protein-coupled receptors (GPCRs), are able to quickly change intracellular cyclic AMP (cAMP) and Ca 2+ levels, and are thought to play important roles in neuropsychiatric and neurodegenerative diseases. Here, we discovered in human neurons an unanticipated presynaptic mechanism that acutely changes synaptic ultrastructure and regulates synaptic communication. Activation of neuromodulator receptors bidirectionally controlled synaptic vesicle numbers within nerve terminals. This control correlated with changes in the levels of cAMP-dependent protein kinase A-mediated phosphorylation of synapsin-1. Using a conditional deletion approach, we reveal that the neuromodulator-induced control of synaptic vesicle numbers was largely dependent on synapsin-1. We propose a mechanism whereby non-phosphorylated synapsin-1 "latches" synaptic vesicles to presynaptic clusters at the active zone. cAMP-dependent phosphorylation of synapsin-1 then removes the vesicles. cAMP-independent dephosphorylation of synapsin-1 in turn recruits vesicles. Synapsin-1 thereby bidirectionally regulates synaptic vesicle numbers and modifies presynaptic neurotransmitter release as an effector of neuromodulator signaling in human neurons., (Copyright © 2019 Elsevier Inc. All rights reserved.)