Febrile seizures were replicated in a mouse model of Dravet syndrome (Scn1a+/−), a condition frequently characterized by l.o.f. mutations to the SCN1A gene, which encodes for NaV1.1 channels highly expressed in PV-INs. Analysis of electrophysiological recordings identified temperature-dependent effects on PV-INs that varied with hippocampal region. Results implicate CA1 as a potential contributor to neural circuit hyperexcitability.

Febrile seizures are recurrent behavioral seizures induced by elevated body temperatures. Occurring in approximately 1 in 20 people, they are quite common. However, the mechanisms underlying hyperexcitability in febrile seizures remain unclear. 

Dravet syndrome, a childhood genetic epilepsy disorder in which patients experience high susceptibility to febrile seizures, can be used to study this condition. Given that about 80% of Dravet syndrome diagnoses are characterized by loss-of-function mutations to the SCN1A gene, febrile seizures can be experimentally modeled in mice with only one functional allele of Scn1a (Scn1a+/−). The SCN1A gene encodes for NaV1.1 (voltage-gated sodium ion channels), which are prevalent in inhibitory interneurons. 

Past experimentation indicates that NaV1.1-related deficits have been implicated in temperature-dependent interneuron dysfunction, facilitating hyperexcitability and thereby seizures. Last summer, I studied NaV1.1 and inhibitory interneuron dysfunction in the subiculum, the ‘output gate’ of the hippocampus which delivers signals to other brain cortices. 

While possible that subicular hyperexcitability drives hyperexcitability elsewhere in the brain, it cannot be assumed that subicular inhibitory interneurons are the sole cause of network hyperexcitability. Inhibitory interneurons in other brain regions may also be affected by temperature-dependent dysfunction.

To examine the impact of increased temperatures on the intrinsic physiology of GABAergic parvalbumin-expressing interneurons (PV-INs) in other hippocampal brain regions, we performed whole cell electrophysiological recordings in PV-INs in the dentate gyrus and CA1 in wildtype and Scn1a+/− mice over a temperature range of 32-42°C. We collected data from mice aged P16-21 (16-21 days postnatal), a developmental timepoint at which Scn1a+/- mice exhibit febrile seizures, while WT mice do not.

We found a temperature-dependent genotypic difference in which Scn1a+/− PV-INs in CA1 entered heat block at elevated temperatures, whereas Scn1a+/− PV-INs in DG did not. Additional, increased temperatures led to decreases in AP amplitude, upstroke velocity/downstroke velocity magnitude, and APD50, and depolarization of resting membrane potential as well as AP threshold for both genotypes in both hippocampal regions.

Febrile seizures do not yet have a cure, and there are no current treatments that adequately address them. Existing treatment options for febrile seizures, which include pharmacological agents and alternatives such as serotonin modulators and first-in-class medications, are palliative approaches. While febrile seizures remain largely unpredictable and unpreventable, it has been shown that early diagnoses and seizure control can lead to better lifelong conditions.

Preliminary temperature ramp recordings of PV-INs in Layers II/III and Layer IV of the neocortex as well as hippocampal area CA3 are ongoing.  may help in attaining a more holistic understanding of the mechanism of febrile seizures, which may reveal potential targets for treatments.