• electrophysiology
• extracellular recording
• gene therapy
• hippocampus
• Lafora disease
• neurodegeneration
• patch-clamp
• striatum
• synaptic plasticity

Lafora Disease (LD) is a rare form of autosomal recessive myoclonus epilepsy which onset occurs during the adolescence as epileptic seizures and evolves into cognitive decline. Mutations in laforin and malin genes, respectively EPM2A and EPM2B (or NHLRC1), account for approx. 88% of known LD cases (Ianzano et al., 2005). In absence of these proteins, normally soluble glycogen contains abnormally long chains which precipitates in aggregates called Lafora bodies (LB). Evidence coming from LD mice model with mutations in Epm2a and Epm2b genes suggest that these mis-branched LB aggregates subtend neurodegeneration and neurological impairment, replicating the patient’s phenotype (Jansen et al., 2007; Burgos et al., 2023; Nitschke et al., 2018). Since monogenic mutations subtend LD pathogenesis, gene therapy can be considered an excellent approach to rescue the pathological phenotype and to restore the physiological synaptic functioning. This therapeutic approach has also been found to rescue the phenotype in several preclinical transgenic mice models of epilepsies (Guan et al., 2022; Street et al., 2023). Recent evidence indicates that the restoration of malin expression in Epm2b-/- mice through gene therapy decreased significantly the accumulation of LBs, increasing their degradation and ameliorating inflammation (Varea et al., 2022). Starting from these assumptions, the aim of this thesis is to characterize membrane properties, synaptic transmission and plasticity, epileptic-like activity, motor and cognitive behavior in a laforin-deficient mice model (Epm2a-/-) before and after replacement gene therapy treatment for laforin. To this aim we will use ex vivo electrophysiological techniques (extracellular and patch-clamp recordings) and behavioral tasks. The investigated areas will be both striatum and hippocampus, brain regions deeply involved in learning (procedural and cognitive) and epileptogenesis processes.