Depolarizing, GABA-mediated synaptic responses and their possible role in epileptiform events; Simulation studies

Abstract

Synaptic transmission controlled by the release of the inhibitory neurotransmitter GABA is generally considered to be the mechanism by which glutamate-mediated excitation is kept under control in the human hippocampus and neocortex. Until recently, epilepsy was thought of as a simple imbalance of neuronal excitation and inhibition. This theory of epileptogenesis has been challenged by the finding that GABA does not always inhibit neuronal activity. Although in adult brain GABA usually induces hyperpolarization of cell membranes, in juvenile brain GABA is depolarizing, bringing the neuronal membrane closer to firing threshold, often enabling action potentials to be triggered. Somewhat surprisingly, GABA-mediated synaptic responses in adult brain tissue can sometimes be excitatory, too. Cohen et al. [I. Cohen, V. Navarro, S. Clemenceau, M. Baulac, R. Miles, On the origin of interictal activity in human temporal lobe epilepsy in vitro, Science 298 (2002) 1418–1421] discovered a subpopulation of excitatory projection cells that exhibited depolarizing GABA responses in slices from epileptic adult subiculum. While most subicular pyramidal cells displayed hyperpolarized behavior in response to GABA, some actually fired bursts of action potentials, in synchrony with the interneurons; the GABA released by the interneurons was only depolarizing for this subset of excitatory cells. These results suggest that it is the interaction between excitatory projection cells depolarized by GABA and interneurons that initiates epileptiform events, at least in subiculum. Interneurons usually seem to provide an inhibitory shield around excitatory neurons. However, when connected to projection cells responding ‘abnormally’ to GABA with depolarization, they may promote paroxysmal synchronizations. A summary of some recent theories and results is presented on possible causes and effects of depolarizing, GABA-mediated synaptic responses in the cerebrum. Special attention is focused on the hippocampal/parahippocampal formation, especially the subicular complex. The subiculum seems to be of particular interest because of its strategic output location to neocortex, and because of the spontaneous, interictal-like activity observed almost exclusively there in slices from patients suffering mesial temporal lobe epilepsy. Simulation results follow, starting from a commonly known GENESIS computer model of a small part of CA3. This ‘CA3’ was re-modeled to more closely resemble a small, ‘subiculum-like’ structure, with a complement of fast-spiking interneurons and three types of projection cells: ‘strong-bursting’, ‘weak-bursting’, and ‘regular-spiking’. Parametric studies of the effects of increasing E GABA A , the GABA reversal potential of certain GABA A receptors, simulate the sometimes excitatory impact of GABAergic signaling. The effects of GABA B receptor impairment in this setting are also briefly considered. Results presented here reinforce experimental evidence that the subiculum has “the right stuff” to play a significant role in epileptiform events.