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Hiperexcitabilidad neuronal: Una clave para desentrañar la disfunción sináptica del hipocampo en la enfermedad de

Cinzia Costa¹, Laura Bellingacci², Jacopo Canonichesi³

¹Section of Neurophysiopathology S.M. della Misericordia Hospital, Section of Neurology and Laboratory of Experimental Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.

|December 18, 2025

Resumen

Se observaron cambios moleculares tempranos en la enfermedad de Lafora (LD), incluida la actividad epiléptica y la plasticidad sináptica alterada, en un modelo de ratón. El tratamiento con cannabidiol mostró beneficios terapéuticos potenciales al reducir la excitabilidad y restaurar la función.

Área de la Ciencia:

Neurociencia
Genética
Biología Molecular

Sus antecedentes:

La enfermedad de Lafora (LD) es un trastorno neurodegenerativo raro y progresivo.
Causada por mutaciones en los genes EPM2A o EPM2B, lo que lleva a la acumulación de cuerpos de Lafora, epilepsia y deterioro cognitivo.
Los mecanismos moleculares tempranos de la LD siguen sin comprenderse por completo.

Objetivo del estudio:

Investigar los cambios electrofisiológicos tempranos en el giro dentado (DG) del modelo de ratón knock-in Epm2a^R240X.
Caracterizar la progresión de la disfunción neuronal y las alteraciones de la plasticidad sináptica en la LD.
Evaluar el potencial terapéutico del cannabidiol (CBD) para mitigar la patología asociada a la LD.

Principales métodos:

Registros electrofisiológicos para evaluar las propiedades de la membrana neuronal, la actividad epiléptica y la plasticidad sináptica (LTP) en ratones Epm2a^R240X a los 1, 3 y 12 meses.
Tinción de ácido periódico-Schiff (PAS) diastasa, inmunofluorescencia y Western blot para detectar cuerpos de Lafora, beta amiloide y subunidades del receptor de glutamato.
Evaluación de los efectos del tratamiento con cannabidiol sobre la excitabilidad y la LTP en ratones de edad avanzada.

Principales resultados:

Se detectó actividad similar a la epilepsia tan pronto como a los 1 mes de edad, aumentando con la edad.
La potenciación a largo plazo (LTP) aberrante, indicativa de disfunción sináptica, apareció a los 3 meses y empeoró a los 12 meses.
El tratamiento con cannabidiol redujo significativamente la excitabilidad neuronal y restauró la LTP en ratones Epm2a^R240X de mayor edad.

Conclusiones:

La sinaptopatía en la enfermedad de Lafora puede ser reversible, incluso en etapas posteriores.
La detección temprana de la hiperexcitabilidad es crucial para una intervención oportuna.
El desarrollo de estrategias terapéuticas efectivas dirigidas a los eventos moleculares tempranos es esencial para el manejo de la LD.

Palabras clave:

enfermedad de Lafora cannabidiol disfunción sináptica del hipocampo hiperexcitabilidad neuronal plasticidad sináptica

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