Age-dependent axonal dysfunctions and altered sharp-wave ripple oscillations in Scn1a ^+/- mice

Mice with Scn1a haploinsufficiency replicate symptoms of Dravet syndrome (DS), a rare childhood disease characterized by febrile seizures at an early age. As adults, patients with DS suffer from epilepsy, motor dysfunction, psychological disorders, and cognitive disabilities. Patients with DS carry loss-of-function variants in the SCN1A gene, which encodes the voltage-gated sodium channel subunit Na_V1.1. As shown in mice, this subunit is mainly expressed in GABAergic cells, especially parvalbumin-expressing interneurons (PV-INs). Consistent with this, interneuron-driven network activities, such as sharp wave ripple oscillations (SPW-R), are altered in Scn1a-deficient mice. By studying network and PV-IN activity during SPW-R in hippocampal slices from Scn1a ^+/- mice, we identified age-dependent impairments in ripple oscillation frequencies and in rhythmic action potential (AP) firing in PV-INs, accompanied by alterations in somatic and axonal AP waveforms. This age-dependent increase in hippocampal cellular and network abnormalities may contribute to the persisting cognitive deficits associated with Scn1a haploinsufficiency.