Modulation of Neurexins Alternative Splicing by Cannabinoid Receptors 1 (CB1) Signaling
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...
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2025-06-01
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| author | Elisa Innocenzi Giuseppe Sciamanna Alice Zucchi Vanessa Medici Eleonora Cesari Donatella Farini David J. Elliott Claudio Sette Paola Grimaldi |
| author_facet | Elisa Innocenzi Giuseppe Sciamanna Alice Zucchi Vanessa Medici Eleonora Cesari Donatella Farini David J. Elliott Claudio Sette Paola Grimaldi |
| author_sort | Elisa Innocenzi |
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| description | 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 <i>Nrxn1</i>–<i>3</i> genes alternative splicing may play an important role in the feedback control of neurotransmission by the endocannabinoid system. |
| format | Article |
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| institution | Kabale University |
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| language | English |
| publishDate | 2025-06-01 |
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| spelling | doaj-art-df1729c798624854896f2341ca7cdd2d2025-08-20T03:28:25ZengMDPI AGCells2073-44092025-06-01141397210.3390/cells14130972Modulation of Neurexins Alternative Splicing by Cannabinoid Receptors 1 (CB1) SignalingElisa Innocenzi0Giuseppe Sciamanna1Alice Zucchi2Vanessa Medici3Eleonora Cesari4Donatella Farini5David J. Elliott6Claudio Sette7Paola Grimaldi8Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, ItalyDepartmental Faculty of Medicine, UniCamillus—Saint Camillus International University of Health and Medical Sciences, 00131 Rome, ItalyDepartment of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, ItalyDepartment of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, 00168 Rome, ItalyGSTeP Organoids Research Core Facility, Fondazione Policlinico A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 00168 Rome, ItalyDepartment of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, ItalyNewcastle University Centre for Cancer, Newcastle University Institute of Biosciences, Newcastle NE1 3BZ, UKDepartment of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, 00168 Rome, ItalyDepartment of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, ItalySynaptic 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 <i>Nrxn1</i>–<i>3</i> genes alternative splicing may play an important role in the feedback control of neurotransmission by the endocannabinoid system.https://www.mdpi.com/2073-4409/14/13/972endocannabinoid systemneurexinalternative splicingcannabinoid receptorshippocampus |
| spellingShingle | Elisa Innocenzi Giuseppe Sciamanna Alice Zucchi Vanessa Medici Eleonora Cesari Donatella Farini David J. Elliott Claudio Sette Paola Grimaldi Modulation of Neurexins Alternative Splicing by Cannabinoid Receptors 1 (CB1) Signaling Cells endocannabinoid system neurexin alternative splicing cannabinoid receptors hippocampus |
| title | Modulation of Neurexins Alternative Splicing by Cannabinoid Receptors 1 (CB1) Signaling |
| title_full | Modulation of Neurexins Alternative Splicing by Cannabinoid Receptors 1 (CB1) Signaling |
| title_fullStr | Modulation of Neurexins Alternative Splicing by Cannabinoid Receptors 1 (CB1) Signaling |
| title_full_unstemmed | Modulation of Neurexins Alternative Splicing by Cannabinoid Receptors 1 (CB1) Signaling |
| title_short | Modulation of Neurexins Alternative Splicing by Cannabinoid Receptors 1 (CB1) Signaling |
| title_sort | modulation of neurexins alternative splicing by cannabinoid receptors 1 cb1 signaling |
| topic | endocannabinoid system neurexin alternative splicing cannabinoid receptors hippocampus |
| url | https://www.mdpi.com/2073-4409/14/13/972 |
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