# Modulation of Neurexins Alternative Splicing by Cannabinoid Receptors 1 (CB1) Signaling

## TL;DR

This study explores how cannabinoid signaling influences the splicing of neurexin genes in the hippocampus, affecting synaptic communication.

## Contribution

The paper reveals a direct crosstalk between CB1 signaling and neurexin alternative splicing, linking endocannabinoid activity to synaptic plasticity.

## Key findings

- CB1 activation with ACEA increases Nrxn1–3 isoforms excluding exon at splice site 4 (SS4−).
- CB1 antagonism with AM251 promotes SS4+ Nrxn variants and increases glutamatergic activity.
- SLM2 knockout eliminates CB1-dependent modulation of neurotransmission and splicing.

## Abstract

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.