The voltage-gated sodium channel Nav1.1 is essential for the proper functioning of inhibitory neurons in the brain. Unfortunately, this channel is known because mutations in the gene encoding it (SCN1a) cause a severe childhood epileptic encephalopathy, Dravet syndrome. Reduced expression has also been linked to cognitive impairment and brain hyperactivity in models of familial Alzheimer's disease.

Dr. Alvarez-Dolado's group from CSIC at CABIMER, in collaboration with Drs. Artigas and Bortolozzi, CSIC and CIBERSAM researchers at IIBB, together with Dr. Meana, CIBERSAM researcher at the University of the Basque Country, and Dr. Esteban from the University of Jaén, have discovered that Nav1.1 dysfunction in the prefrontal cortex (PFC) of the brain during adolescence not only causes epilepsy, but also induces severe depressive symptomatology.  The results, published in the prestigious journal Brain, show that Nav1.1 is necessary for the proper development of cognitive and emotional functions dependent on the PFC.  Dysfunction of Nav1.1 during adolescence in mice causes an imbalance of the arousal/inhibition ratio in the CPF, leading to a pattern of gene expression closely related to major depression, reduced serotonin levels, and memory impairment. In addition, interestingly, patients with major depression have low expression levels of this channel.

These findings open the door to the design of new drugs that specifically activate Nav1.1 for use as antidepressants in a novel and more effective way. In addition, the work identifies CPF and adolescence as critical elements to consider in the development of Dravet syndrome symptoms and provides new clues to understanding why patients with epilepsy often also develop depression. This provides new opportunities to better understand and treat Alzheimer's disease, epilepsy and depression.

The work has been funded by the MCIU/AEI/FEDER, UE Grants, Dravet Support and STXBP1 Syndrome Associations, Alicia Koplowitz and La Marató TV3 Foundations, CIBERSAM and the Governments of Andalusia, Catalonia and the Basque Country.

 

Scn1a haploinsufficiency in the prefrontal cortex engages to cognitive impairment and depressive phenotype. Riga MS, Pérez-Fernández M, Miquel-Rio L, Paz V, Campa L, Martínez-Losa M, Esteban FJ, Callado LF, Meana J, Artigas F, Bortolozzi A, Álvarez-Dolado M. Brain. 2024 May 21:awae167. PMID: 38769595.

https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awae167...