Abstract
Neurexins are presynaptic cell-adhesion molecules essential for synaptic function that are expressed in thousands of alternatively spliced isoforms. Recent studies suggested that alternative splicing at splice site 4 (SS4) of Nrxn1 is tightly regulated by an activity-dependent mechanism. 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. However, conflicting results confound the assessment of neurexin alternative splicing, prompting us to re-evaluate this issue. 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. in vivo, systemic kainate-induced activation of neurons in the hippocampus produced no changes in Nrxn1-SS4 alternative splicing. 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. 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.
Highlights
Neurexins are presynaptic cell-adhesion molecules that play crucial role in defining synapse properties through differential interactions with multifarious extra- and intra-cellular ligands
Semi-quantitative RT-PCR of Nrxn1 splice site 4 (SS4) splicing revealed a significant change in the Nrxn1SS4 splicing ratio, with an increasing preponderance of the SS4+ form associated with increasing KCl concentrations (Figures 1B,C)
This study was initiated to explore the mechanistic basis for the activity-dependent alternative splicing of neurexins at SS4, which is of interest because it regulates the glutamate receptor composition of synapses (Aoto et al, 2013; Dai et al, 2019)
Summary
Neurexins are presynaptic cell-adhesion molecules that play crucial role in defining synapse properties through differential interactions with multifarious extra- and intra-cellular ligands. 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). Both SS4+ and SS4– neurexins bind to neuroligins, albeit with differential affinities (Boucard et al, 2005; Chih et al, 2006; Comoletti et al, 2006). At least for some synapses, neurexin SS4 alternative splicing is of central importance in controlling synapse properties
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