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Lookup NU author(s): Professor David ElliottORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 by the authors. Synaptic plasticity is the key mechanism underlying learning and memory. Neurexins are pre-synaptic molecules that play a pivotal role in synaptic plasticity, interacting with many different post-synaptic molecules in the formation of neural circuits. Neurexins are alternatively spliced at different splice sites, yielding thousands of isoforms with different properties of interaction with post-synaptic molecules for a quick adaptation to internal and external inputs. The endocannabinoid system also plays a central role in synaptic plasticity, regulating key retrograde signaling at both excitatory and inhibitory synapses. This study aims at elucidating the crosstalk between alternative splicing of neurexin and the endocannabinoid system in the hippocampus. By employing an ex vivo hippocampal system, we found that pharmacological activation of cannabinoid receptor 1 (CB1) with the specific agonist ACEA led to reduced neurotransmission, associated with increased expression of the Nrxn1–3 spliced isoforms excluding the exon at splice site 4 (SS4−). In contrast, treatment with the CB1 antagonist AM251 increased glutamatergic activity and promoted the expression of the Nrxn variants including the exon (SS4+) Knockout of the involved splicing factor SLM2 determined the suppression of the exon splicing at SS4 and the expression only of the SS4+ variants of Nrxns1–3 transcripts. Interestingly, in SLM2 ko hippocampus, modulation of neurotransmission by AM251 or ACEA was abolished. These findings suggest a direct crosstalk between CB1-dependent signaling, neurotransmission and expression of specific Nrxns splice variants in the hippocampus. We propose that the fine-tuned regulation of Nrxn1–3 genes alternative splicing may play an important role in the feedback control of neurotransmission by the endocannabinoid system.
Author(s): Innocenzi E, Sciamanna G, Zucchi A, Medici V, Cesari E, Farini D, Elliott DJ, Sette C, Grimaldi P
Publication type: Article
Publication status: Published
Journal: Cells
Year: 2025
Volume: 14
Issue: 13
Online publication date: 25/06/2025
Acceptance date: 19/06/2025
Date deposited: 28/07/2025
ISSN (electronic): 2073-4409
Publisher: MDPI
URL: https://doi.org/10.3390/cells14130972
DOI: 10.3390/cells14130972
Data Access Statement: The original contributions presented in this study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.
PubMed id: 40643493
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