Scn1a dysfunction alters behavior but not the effect of stress on seizure response

Abstract

Mutations in the voltage-gated sodium channel gene SCN1A are responsible for a number of epilepsy disorders, including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome. In addition, dysfunction in SCN1A is increasingly being linked to neuropsychiatric abnormalities, social deficits and cognitive disabilities. We have previously reported that mice heterozygous for the SCN1A R1648H mutation identified in a GEFS+ family have infrequent spontaneous seizures, increased susceptibility to chemically and hyperthermia-induced generalized seizures and sleep abnormalities. In this study, we characterized the behavior of heterozygous mice expressing the SCN1A R1648H mutation (Scn1a(RH/+)) and the effect of stress on spontaneous and induced seizures. We also examined the effect of the R1648H mutation on the hypothalamic-pituitary-adrenal (HPA) axis response. We confirmed our previous finding that Scn1a(RH/+) mutants are hyperactive, and also identified deficits in social behavior, spatial memory, cued fear conditioning, pre-pulse inhibition and risk assessment. Furthermore, while exposure to a stressor did increase seizure susceptibility, the effect seen in the Scn1a(RH/+) mutants was similar to that seen in wild-type littermates. In addition, Scn1a dysfunction does not appear to alter HPA axis function in adult animals. Our results suggest that the behavioral abnormalities associated with Scn1a dysfunction encompass a wider range of phenotypes than previously reported and factors such as stress exposure may alter disease severity in patients with SCN1A mutations.

Early-life febrile seizures worsen adult phenotypes in Scn1a mutants

“…Yu et al (2006) demonstrated that Scn1a knockout mice on an advanced (N10) C57BL6/J background display more severe phenotypes compared to those on a mixed 129/SvJ:C57BL6/J background. We also observed that RH/+ mutants at the N12 generation had a higher mortality rate than at the N2 generation (Sawyer et al 2016). Taken together, these results demonstrate that both genetic factors and environmental factors such as exposure to early life FSs are risk factors for the development of behavioral impairments in Scn1a mutant mice.…”

“…In addition, our current study utilized mutant mice on a more advanced C57BL/6J genetic background. The C57BL/6J genetic background was previously shown to increase the severity of seizure phenotypes in Scn1a mutants (Yu et al 2006, Sawyer et al 2016). …”

“…However, the association between recurrent and prolonged early-life FSs and the development of these clinically challenging phenotypes in patients with SCN1A mutations remains unclear and has never been experimentally investigated. Rodent models of Scn1a dysfunction recapitulate many of the cognitive and behavioral deficits reported in patients and therefore provide an opportunity to investigate this relationship (Han et al 2012, Ito et al 2013, Ohmori et al 2014, Sawyer et al 2016). While behavior was unaltered in Scn1a RH/+ controls and WT littermates that were subjected to the A/PFE paradigm, early-life FS exposure in Scn1a RH/+ mutants led to hyperactivity, deficits in social behaviors and impairments in recognition memory during adulthood, demonstrating the increased risk conferred by the SCN1A mutation.…”

“…The RH/+ mutants that were used in the current study were backcrossed to C57BL/6J for 4 generations. In contrast, our previous behavioral studies were conducted on RH/+ mutants what were backcrossed to C57BL/6J for 11-13 generations (Purcell et al 2013, Sawyer et al 2016). Yu et al (2006) demonstrated that Scn1a knockout mice on an advanced (N10) C57BL6/J background display more severe phenotypes compared to those on a mixed 129/SvJ:C57BL6/J background.…”

Effect of Seizures on the Developing Brain and Cognition

“…30 Additional assessments of cognition have shown deficits in the memory requiring components of context-dependent fear conditioning. 29,30 Behavioral tests in the GEFS+ model have been similar to those seen in the Dravet models, including hyperactivity, impaired social performance, and deficits in spatial memory 32 . In addition deficits in cued fear conditioning and risk assessment have also been reported in this model 32 .…”