(2011) showed that Nrxn2 and Nrxn3 alternative splicing at SS3 is modulated by neuronal depolarization induced by high KCl (50 mM). Subsequently, Rozic-Kotliroff and Zisapel (2007) and Rozic et al. Gorecki et al., were the first to investigate the regulation of neurexin alternative splicing using kainic acid (KA) and pentylenetetrazole (PTZ) stimulation, but concluded that alternative splicing of Nrxn2 at SS1–SS4 was not activity-dependent ( Gorecki et al., 1999). Several studies reported that alternative splicing of neurexins is activity-dependent ( Gorecki et al., 1999 Rozic-Kotliroff and Zisapel, 2007 Iijima et al., 2011 Rozic et al., 2011 Ding et al., 2017). Thus, at least for some synapses, neurexin SS4 alternative splicing is of central importance in controlling synapse properties. In hippocampal synapses, presynaptic Nrxn1 and Nrxn3 SS4 splice variants control, respectively, the postsynaptic NMDA- and AMPA-receptor content by a trans-synaptic mechanism ( Aoto et al., 2013 Dai et al., 2019). Both SS4+ and SS4– neurexins bind to neuroligins, albeit with differential affinities ( Boucard et al., 2005 Chih et al., 2006 Comoletti et al., 2006). SS4– neurexins bind to LRRTMs ( Sugita et al., 2001 Ko et al., 2009 Siddiqui et al., 2010 Boucard et al., 2012), whereas SS4+ neurexins bind to cerebellins ( Uemura et al., 2010 Matsuda and Yuzaki, 2011). The two alternatively spliced SS4 variants either contain (SS4+) or lack a 90 bp sequences that is encoded by the alternatively spliced SS4 exon ( Tabuchi and Sudhof, 2002). Six canonical sites of alternative splicing (SS1–SS6) are known, of which SS1, SS2, SS3, and SS6 are specific to α-neurexins, whereas SS4 and SS5 exist in both α- and β-neurexins ( Ullrich et al., 1995).Īmong the sites of neurexin alternative splicing, SS4 has been most intensely studied. Neurexin genes ( Nrxn1, Nrxn2, and Nrxn3 in mice) use alternative promotors to transcribe distinct isoforms (α, β, γ), whose mRNAs are subject to extensive alternative splicing in patterns that are specific to neuronal cell types ( Treutlein et al., 2014 Fuccillo et al., 2015 Furlanis et al., 2019 Lukacsovich et al., 2019). Genetic perturbation of neurexins and their ligands are implicated in multiple neuropsychiatric disorders ( Sudhof, 2017 Kasem et al., 2018 Gomez et al., 2021). Neurexins are presynaptic cell-adhesion molecules that play crucial role in defining synapse properties through differential interactions with multifarious extra- and intra-cellular ligands. Our results suggest that although Nrxn1-SS4 alternative splicing may represent a mechanism of activity-dependent synaptic plasticity, common procedures for testing this hypothesis are prone to artifacts, and more sophisticated approaches will be necessary to test this important question. Moreover, focal kainate injections into the mouse cerebellum induced small changes in Nrxn1-SS4 alternative splicing that, however, were associated with large decreases in Nrxn1 expression and widespread DNA damage. in vivo, systemic kainate-induced activation of neurons in the hippocampus produced no changes in Nrxn1-SS4 alternative splicing. We find that in cortical cultures, membrane depolarization by elevated extracellular K +-concentrations produced an apparent shift in Nrxn1-SS4 alternative splicing by inducing neuronal but not astroglial cell death, resulting in persistent astroglial Nrxn1-SS4+ expression and decreased neuronal Nrxn1-SS4– expression. However, conflicting results confound the assessment of neurexin alternative splicing, prompting us to re-evaluate this issue. Given that Nrxn1 alternative splicing at SS4 controls NMDA-receptor-mediated synaptic responses, activity-dependent SS4 alternative splicing would suggest a new synaptic plasticity mechanism. Recent studies suggested that alternative splicing at splice site 4 (SS4) of Nrxn1 is tightly regulated by an activity-dependent mechanism. Neurexins are presynaptic cell-adhesion molecules essential for synaptic function that are expressed in thousands of alternatively spliced isoforms. 2Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, United States.1Howard Hughes Medical Institute, Stanford University, Stanford, CA, United States.
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