Cellular Mechanisms of Desynchronizing Effects of Hypothermia in an In Vitro Epilepsy Model

Gholam K. Motamedi*, Alfredo Gonzalez Sulser, Rhonda Dzakpasu, Stefano Vicini

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Hypothermia can terminate epileptiform discharges in vitro and in vivo epilepsy models. Hypothermia is becoming a standard treatment for brain injury in infants with perinatal hypoxic ischemic encephalopathy, and it is gaining ground as a potential treatment in patients with drug resistant epilepsy. However, the exact mechanism of action of cooling the brain tissue is unclear. We have studied the 4-aminopyridine model of epilepsy in mice using single- and dual-patch clamp and perforated multi-electrode array recordings from the hippocampus and cortex. Cooling consistently terminated 4-aminopyridine induced epileptiform-like discharges in hippocampal neurons and increased input resistance that was not mimicked by transient receptor potential channel antagonists. Dual-patch clamp recordings showed significant synchrony between distant CA1 and CA3 pyramidal neurons, but less so between the pyramidal neurons and interneurons. In CA1 and CA3 neurons, hypothermia blocked rhythmic action potential discharges and disrupted their synchrony; however, in interneurons, hypothermia blocked rhythmic discharges without abolishing action potentials. In parallel, multi-electrode array recordings showed that synchronized discharges were disrupted by hypothermia, whereas multi-unit activity was unaffected. The differential effect of cooling on transmitting or secreting gamma-aminobutyric acid interneurons might disrupt normal network synchrony, aborting the epileptiform discharges. Moreover, the persistence of action potential firing in interneurons would have additional antiepileptic effects through tonic gamma-aminobutyric acid release.

Original languageEnglish
Pages (from-to)199-209
Number of pages11
JournalNeurotherapeutics
Volume9
Issue number1
DOIs
Publication statusPublished - Jan 2012

Keywords

  • Hypothermia
  • Epilepsy
  • Interneuron
  • Synchrony
  • GABA
  • EPILEPTIFORM ACTIVITY
  • TEMPERATURE-DEPENDENCE
  • HIPPOCAMPAL SLICES
  • RUTHENIUM RED
  • SEIZURES
  • NEURONS
  • CHANNEL
  • 4-AMINOPYRIDINE
  • TERMINATION
  • INHIBITION

Cite this