A new model for prenatal brain damage. I. GABAA receptor activation induces cell death in developing rat hippocampus

Exp Neurol. 2003 Jun;181(2):258-69. doi: 10.3201/eid0906.030118.

Abstract

Premature infants are at exceptionally high risk for hypoxic-ischemic insults and other traumatic events that result in permanent brain damage. However, no current models adequately mimic these events. An emerging concept is that the major excitatory drive in immature neurons is derived from depolarizing responses following activation of the gamma-aminobutyric acid (GABA)(A) receptor, resulting in the opening of voltage-sensitive calcium channels. While calcium-mediated signal transduction is trophic in developing neurons, excessive calcium entry is a major mediator of excitotoxicity. We report that exogenous activation of GABA(A) receptors by muscimol in newborn rats increases cell death in the hippocampus. The effects are region specific, persistent, and greater in males. Muscimol-induced damage is prevented by pretreatment with diltiazem, an L-type voltage-sensitive calcium channel blocker. Results using hippocampal cultures parallel those observed in vivo, indicating that the effects are mediated directly in the hippocampus. Existing models of pediatric hypoxic-ischemic brain damage focus on the effects of glutamate in the postnatal day 7 rat, because it is considered analogous to the newborn human. This makes the newborn rat analogous to the late gestational human. Ischemia in newborn rats induces GABA release and we propose that treatment with muscimol mimics the cell death cascade induced by hypoxia-ischemia in premature human infants.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Animals, Newborn
  • Brain Damage, Chronic / chemically induced
  • Brain Damage, Chronic / pathology
  • Brain Damage, Chronic / physiopathology*
  • Calcium / metabolism
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels, L-Type / metabolism
  • Cell Count
  • Cell Death / drug effects
  • Cells, Cultured
  • Diltiazem / pharmacology
  • Disease Models, Animal
  • Female
  • GABA Agonists
  • GABA-A Receptor Agonists
  • Hippocampus / pathology
  • Hippocampus / physiopathology*
  • L-Lactate Dehydrogenase / metabolism
  • Male
  • Muscimol
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA-A / metabolism*
  • Sex Factors

Substances

  • Calcium Channel Blockers
  • Calcium Channels, L-Type
  • GABA Agonists
  • GABA-A Receptor Agonists
  • Receptors, GABA-A
  • Muscimol
  • L-Lactate Dehydrogenase
  • Diltiazem
  • Calcium