NEUROBIOLOGY Tilting the Balance

Cortical function depends on the proper balance between excitation and inhibition: If the balance tilts toward excitation, a seizure may occur, whereas if the balance shifts too far toward inhibition, network activity may shut down. GABA (-aminobutyric acid) is the major inhibitory transmitter in the adult brain; however, GABA is excitatory during early development, leading Bernard et al. to investigate the possible inhibitory role of endocannabinoids in regulating network activity in the developing brain. After using immunocytochemistry to localize cannabinoid type 1 (CB1) receptors to the terminals of hippocampal GABAergic interneurons, the authors combined electrophysiology with pharmacological analysis to show that endocannabinoids released from pyramidal cells and interneurons in rat pup hippocampal slices could act through CB1 receptors to inhibit GABA release. Pharmacological analysis in the presence of glutamate antagonists indicated that CB1 receptors were tonically activated in hippocampal slices and that CB1 blockade enhanced the amplitude of spontaneous GABAergic postsynaptic currents and stimulated the appearance of spontaneous epileptiform discharges, whereas endocannabinoid accumulation decreased the spontaneous firing rate of interneurons. In the absence of glutamatergic antagonists, CB1 blockade stimulated network activity and CB1 stimulation inhibited network activity. A CB1 antagonist triggered epileptic discharges in 5-day-old rat pups in vivo, whereas pharmacological activation of CB1 receptors decreased spontaneous neuronal activity. Thus, the authors conclude that endocannabinoid signaling acts to regulate network activity in the developing brain and that its disruption could have major functional consequences.

C. Bernard, M. Milh, Y. M. Morozov, Y. Ben-Ari, T. F. Freund, H. Gozlan, Altering cannabinoid signaling during development disrupts neuronal activity. Proc. Natl. Acad. Sci. U.S.A. 102, 9388-9393 (2005). [Abstract] [Full Text]