Developmental alterations in firing properties of hippocampal CA1 inhibitory and excitatory neurons in a mouse model of Dravet syndrome

Neurobiol Dis. 2021 Jan;148:105209. doi: 10.1016/j.nbd.2020.105209. Epub 2020 Nov 30.

Abstract

Dravet syndrome (Dravet) is a rare, severe childhood-onset epilepsy, caused by heterozygous de novo mutations in the SCN1A gene, encoding for the alpha subunit of the voltage-gated sodium channel, NaV1.1. The neuronal basis of Dravet is debated, with evidence favoring reduced function of inhibitory neurons, that might be transient, or enhanced activity of excitatory cells. Here, we utilized Dravet mice to trace developmental changes in the hippocampal CA1 circuit, examining the properties of CA1 horizontal stratum-oriens (SO) interneurons and pyramidal neurons, through the pre-epileptic, severe and stabilization stages of Dravet. Our data indicate that reduced function of SO interneurons persists from the pre-epileptic through the stabilization stages, with the greatest functional impairment observed during the severe stage. In contrast, opposing changes were detected in CA1 excitatory neurons, with a transient increase in their excitability during the pre-epileptic stage, followed by reduced excitability at the severe stage. Interestingly, alterations in the function of both inhibitory and excitatory neurons were more pronounced when the firing was evoked by synaptic stimulation, implying that loss of function of NaV1.1 may also affect somatodendritic functions. These results suggest a complex pathophysiological mechanism and indicate that the developmental trajectory of this disease is governed by reciprocal functional changes in both excitatory and inhibitory neurons.

Keywords: CA1 pyramidal neurons; CA1 stratum-oriens interneurons; Dravet syndrome; Epilepsy; Scn1a.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology*
  • Animals
  • CA1 Region, Hippocampal / metabolism*
  • CA1 Region, Hippocampal / physiopathology
  • Disease Models, Animal
  • Disease Progression
  • Epilepsies, Myoclonic / genetics
  • Epilepsies, Myoclonic / metabolism*
  • Epilepsies, Myoclonic / physiopathology
  • Interneurons / metabolism*
  • Interneurons / physiology
  • Mice
  • NAV1.1 Voltage-Gated Sodium Channel / genetics
  • Neurons
  • Pyramidal Cells / metabolism*
  • Pyramidal Cells / physiology
  • Seizures / genetics
  • Seizures / metabolism
  • Seizures / physiopathology

Substances

  • NAV1.1 Voltage-Gated Sodium Channel
  • Scn1a protein, mouse