期刊
FRONTIERS IN MOLECULAR NEUROSCIENCE
卷 14, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fnmol.2021.659681
关键词
neurexins; alternative splicing; cFos; cell dealth; depolarization; kainate; cerebellum; hippocampus
资金
- National Institute of Mental Health [MH052804, MH116529]
- European Molecular Biology Organization Long Term Fellowship [ALTF 803-2017]
- Larry L. Hillblom Foundation [2020-A-016-FEL]
This study explores the alternative splicing of the presynaptic cell-adhesion molecules Neurexins, particularly focusing on Nrxn1 at splice site 4 (SS4) and its potential link to activity-dependent synaptic plasticity. However, conflicting results and potential artifacts in common testing procedures call for more sophisticated approaches to address this important question.
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.
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