strychnine and 4-amino-2-methylquinoline

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 γ-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 γ-aminobutyric acid release.

Topics: Action Potentials; Aminoquinolines; Animals; Animals, Newborn; Bicuculline; Biophysics; Cerebral Cortex; Convulsants; Electric Stimulation; Evoked Potentials; Excitatory Amino Acid Antagonists; GABA-A Receptor Antagonists; Glutamate Decarboxylase; Green Fluorescent Proteins; Hippocampus; Hypothermia, Induced; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neural Pathways; Neurons; Organ Culture Techniques; Patch-Clamp Techniques; Phorbol Esters; Quinaldines; Quinoxalines; Sodium Channel Blockers; Strychnine; Temperature; Tetrodotoxin