Genetic and pharmacological modulation of giant depolarizing potentials in the neonatal hippocampus associates with increased seizure susceptibility

J Physiol. 2013 Jan 1;591(1):57-65. doi: 10.1113/jphysiol.2012.234674. Epub 2012 Sep 24.

Abstract

The expression of Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) is responsible for high intracellular Cl(-) resulting in the excitatory action of GABA(A) receptor activation in the developing brain. Giant depolarizing potentials (GDPs) are spontaneous network oscillations that involve GABA(A) receptors and are thought to be important in establishing neuronal circuit wiring. Earlier work established that seizure susceptibility in the GABA(A) γ2(R43Q) epilepsy mouse is impacted by developmental consequences of impaired GABA(A) receptor function. We investigated the potential mechanism of the developmental influence by recording GDPs in the CA3 pyramidal neurons from brain slices of the neonatal GABA(A) γ2(R43Q) mouse. Interestingly, the number of GPDs was significantly lower in slices from mutant mouse compared with wild-type control, suggesting an involvement in setting seizure susceptibility. To test this idea we blocked NKCC1 with bumetanide in neonatal mice and reduced the number of GDPs to a level similar to that seen in the mutant mice. We found that neonatal treatment with bumetanide resulted in a similar level of susceptibility to thermally induced seizures as described for the GABA(A) γ2(R43Q) mouse. These results provide evidence that a human GABA(A) receptor epilepsy mutation exerts a developmental influence by modulating the number of GDPs. It also draws attention to the potential risk of early treatment with bumetanide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Bumetanide / pharmacology
  • Disease Models, Animal
  • Epilepsy / physiopathology*
  • Hippocampus / physiopathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mutation
  • Receptors, GABA-A / physiology*

Substances

  • Receptors, GABA-A
  • Bumetanide