Scn1a missense mutation impairs GABAA receptor-mediated synaptic transmission in the rat hippocampus

Mutations of the Nav1.1 channel subunit SCN1A have been implicated in the pathogenesis of human febrile seizures (FS). We have recently developed hyperthermia-induced seizure-susceptible (Hiss) rat, a novel rat model of FS, which carries a missense mutation (N1417H) in Scn1a [1]. Here, we conducted electrophysiological studies to clarify the influences of the Scn1a mutation on the hippocampal synaptic transmission, specifically focusing on the GABAergic system. Hippocampal slices were prepared from Hiss or F344 (control) rats and maintained in artificial cerebrospinal fluid saturated with 95% O2 and 5% CO2in vitro. Single neuron activity was recorded from CA1 pyramidal neurons and their responses to the test (unconditioned) or paired pulse (PP) stimulation of the Schaffer collateral/commissural fibers were evaluated. Hiss rats were first tested for pentylenetetrazole-induced seizures and confirmed to show high seizure susceptibility to the blockade of GAGAA receptors. The Scn1a mutation in Hiss rats did not directly affect spike generation (i.e., number of evoked spikes and firing threshold) of the CA1 pyramidal neurons elicited by the Schaffer collateral/commissural stimulation. However, GABAA receptor-mediated inhibition of pyramidal neurons by the PP stimulation was significantly disrupted in Hiss rats, yielding a significant increase in the number of PP-induced firings at PP intervals of 32–256 ms. The present study shows that the Scn1a missense mutation preferentially impairs GABAA receptor-mediated synaptic transmission without directly altering the excitability of the pyramidal neurons in the hippocampus, which may be linked to the pathogenesis of FS.

Research highlights
► Hiss rats are the new seizure model carrying a missense (N1417H) mutation of Scn1a.
► Scn1a mutation enhances seizure susceptibility to pentylenetetrazole.
► Scn1a mutation does not directly alter the excitability of CA1 pyramidal neurons.
► Scn1a mutation impairs GABAA receptor-mediated inhibition of CA1 pyramidal neurons.