Epm2aR240X knock-in mice present earlier cognitive decline and more epileptic activity than Epm2a−/− mice

• Published in: Neurobiology of disease 2023-06, Vol.181, p.106119-106119, Article 106119
• Main Authors: Burgos, Daniel F., Sciaccaluga, Miriam, Worby, Carolyn A., Zafra-Puerta, Luis, Iglesias-Cabeza, Nerea, Sánchez-Martín, Gema, Prontera, Paolo, Costa, Cinzia, Serratosa, José M., Sánchez, Marina P.
• Format: Article
• Language: English
• Subjects: Electrophysiology; Epilepsy; Knock-in mouse; Lafora disease; Laforin; Neurodegeneration; Neuroinflammation; Progressive; Video-EEG
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2023.106119

Lafora disease is a rare recessive form of progressive myoclonic epilepsy, usually diagnosed during adolescence. Patients present with myoclonus, neurological deterioration, and generalized tonic-clonic, myoclonic, or absence seizures. Symptoms worsen until death, usually within the first ten years of clinical onset. The primary histopathological hallmark is the formation of aberrant polyglucosan aggregates called Lafora bodies in the brain and other tissues. Lafora disease is caused by mutations in either the EPM2A gene, encoding laforin, or the EPM2B gene, coding for malin. The most frequent EPM2A mutation is R241X, which is also the most prevalent in Spain. The Epm2a‐/− and Epm2b−/− mouse models of Lafora disease show neuropathological and behavioral abnormalities similar to those seen in patients, although with a milder phenotype. To obtain a more accurate animal model, we generated the Epm2aR240X knock-in mouse line with the R240X mutation in the Epm2a gene, using genetic engineering based on CRISPR-Cas9 technology. Epm2aR240X mice exhibit most of the alterations reported in patients, including the presence of LBs, neurodegeneration, neuroinflammation, interictal spikes, neuronal hyperexcitability, and cognitive decline, despite the absence of motor impairments. The Epm2aR240X knock-in mouse displays some symptoms that are more severe that those observed in the Epm2a−/− knock-out, including earlier and more pronounced memory loss, increased levels of neuroinflammation, more interictal spikes and increased neuronal hyperexcitability, symptoms that more precisely resemble those observed in patients. This new mouse model can therefore be specifically used to evaluate how new therapies affects these features with greater precision. [Display omitted] •When compared to Epm2a−/− mice, Epm2aR240X knock-in mice.•Present earlier cognitive decline.•More neuroinflammation and epileptic activity.•Similar number of Lafora bodies and neurodegeneration.•The Epm2aR240X mouse appears to be a better model to study some aspects of the disease.