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

Increasing evidence suggests that subcortical structures contribute to seizure susceptibility and cognitive impairment in several epileptic syndromes. However, research into mechanisms linking neuronal excitability and synaptic dysfunction in epilepsy has mainly focused on the cortex and hippocampus, leaving basal ganglia contributions largely unexplored. Using a genetic murine model of Lafora disease (LD), a drug-resistant form of neurodegenerative epilepsy, we performed ex vivo patch-clamp recordings to assess neuronal excitability, synaptic transmission, and plasticity of striatal medium spiny neurons. Our results reveal progressive alterations in corticostriatal transmission and long-term synaptic plasticity, including long-term potentiation (LTP). Electrophysiological and biochemical assessments showed a reduced NMDA/AMPA ratio and reduced expression of NMDA receptor subunits and dopamine receptors in striatal neurons of LD mice. Exposure to a dopamine D2 receptor agonist and to cannabidiol restored long-term plasticity in LD mice, suggesting a D2R- and CB2R-dependent synergic action on striatal LTP. Our findings highlight basal ganglia dysfunction in experimental epilepsy and suggest an unconventional dopaminergic-endocannabinoid interplay.