D2 dopamine and CB2 cannabinoid receptor cooperation restores striatal LTP in an epilepsy model.

Sciaccaluga M.; Bellingacci L.; Imperatore V.; Taddei A.; Tozzi A.; Di Filippo M.; Barzasi M.; Gardoni F.; Sánchez M.; Serratosa J. et al. · Neurobiology of disease · 2026

**Background & Methods** This study utilized a genetic murine model of Lafora disease (LD), a drug-resistant neurodegenerative epilepsy, to investigate basal ganglia dysfunction in epilepsy. Ex vivo patch-clamp electrophysiology was performed on striatal medium spiny neurons to assess neuronal excitability, synaptic transmission, and long-term synaptic plasticity, complemented by biochemical analyses of receptor expression and function. **Key Findings** • Progressive alterations in corticostriatal transmission and long-term potentiation (LTP) were observed in LD mice, with reduced NMDA/AMPA receptor ratios and decreased expression of NMDA receptor subunits and dopamine receptors in striatal neurons compared to controls. • Exposure to a dopamine D2 receptor agonist and cannabidiol (CBD) synergistically restored long-term synaptic plasticity and LTP in LD striatal neurons, demonstrating a D2 dopamine receptor and CB2 cannabinoid receptor-dependent cooperative mechanism. • These findings suggest that basal ganglia dysfunction, particularly impaired striatal synaptic plasticity, contributes to seizure susceptibility and cognitive impairment in epilepsy, and that dopaminergic-endocannabinoid interactions represent a novel therapeutic target. **Dosage & Administration** Not reported. The abstract does not specify concentrations, exposure durations, or administration protocols for the D2 receptor agonist or cannabidiol. **Safety & Adverse Effects** Not reported. The study focused on electrophysiological restoration of LTP without addressing safety profiles or adverse effects of the tested compounds. **Evidence Quality** This research represents preliminary mechanistic work in an animal model with significant limitations. As a genetic murine model study, findings require validation in additional disease models and translation to human epilepsy. The ex vivo electrophysiology approach, while providing detailed synaptic mechanisms, does not establish in vivo seizure reduction or behavioral outcomes. The study's focus on a single epilepsy model (Lafora disease) limits generalizability to other epileptic syndromes. The review article format suggests this represents a synthesis of findings rather than a primary research report. Further clinical trials would be necessary to establish therapeutic efficacy, optimal dosing, safety profiles, and clinical relevance of D2-CB2 receptor cooperation in human epilepsy management.

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