Neuronal hyperexcitability: A key to unraveling hippocampal synaptic dysfunction in Lafora disease

Background and Objective: Lafora disease (LD) is a rare progressive disorder caused by mutations in the EPM2A or EPM2B genes, characterized by the accumulation of Lafora bodies, drug-resistant epilepsy, and cognitive decline. To investigate the early molecular mechanisms of LD, we studied electrophysiological changes in the dentate gyrus (DG) of the Epm2aR240X knock-in mouse model at various ages. Methods: Electrophysiological recordings measured neuronal membrane properties, epileptic-like activity, epileptic thresholds, and synaptic plasticity in Epm2aR240X mice at 1, 3, and 12 months. We also employed Periodic Acid–Schiff (PAS) diastase staining, immunofluorescence, and Western blotting to detect Lafora bodies, amyloid beta deposition, and the expression of glutamate receptor subunits. Results: Epileptic-like activity began at 1 month and intensified with age. Aberrant long-term potentiation (LTP) appeared at 3 months and worsened by 12 months. Notably, cannabidiol treatment reduced excitability and restored LTP in older mice, suggesting its potential therapeutic value. Significance: The reversibility of synaptopathy, even at advanced stages, reinforces the importance of early detection of hyperexcitability and the development of effective therapeutic approaches.