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.