Rationale:
Dravet syndrome (DS) is a severe epileptic encephalopathy, characterized by drug-resistant epilepsy, severe cognitive and behavioral deficits, with an increased risk of sudden unexpected death (SUDEP). It is caused by haploinsufficiency of
SCN1A gene encoding for the α-subunit of the voltage-gated sodium channel Na
v1.1. Therapeutic approaches aiming to up-regulate the healthy copy of
SCN1A gene to restore its normal expression levels are being developed. However, whether
Scn1a gene function is required only during a specific developmental time-window or, alternatively, if its physiological expression is necessary in adulthood is untested up to now.
Methods:
We induced Scn1a gene haploinsufficiency at two ages spanning postnatal brain development (day 30, P30 and day 60, P60) and compared the phenotypes of those mice to Scn1a perinatally induced mice (P2), recapitulating all deficits of DS mice.
Results:
Induction
of heterozygous Na
v1.1 mutation at P30 and P60 elicited susceptibility to the development of both spontaneous and febrile seizures and SUDEP rates comparable to P2-induced mice, with symptom onset accompanied by the characteristic GABAergic interneuron dysfunction. Finally, delayed
Scn1a haploinsufficiency induction provoked hyperactivity, anxiety, and social attitude impairment at levels comparable to age matched P2-induced mice, while
it was associated with a better cognitive performance, with P60-induced mice behaving like control group.
Conclusions:
Our data show that maintenance of physiological levels of Na
v1.1 after brain development is not sufficient to prevent DS symptoms and that long-lasting restoration of
Scn1a gene expression would be required
to grant optimal clinical benefit in DS patients.
Funding:
This work was supported by Telethon GGP19249 to Gaia Colasante