Cholinergic involvement in the GABAergic regulation of inhibition in the hippocampus

Abstract

Synaptic inhibition modulates neuronal excitability. In addition, synaptic inhibition itself can be modulated. Hippocampal pyramidal cells undergo a process called depolarization-induced suppression of inhibition (DSI), in which a brief depolarization of the pyramidal cell results in a transient decrease in GABA A-receptor-mediated inhibition in that cell. DSI is initiated in the pyramidal cell, but is expressed presynaptically as a decrease in GABA release from the interneurons synapsing with that cell. DSI of spontaneous, action-potential-dependent, inhibitory postsynaptic currents (sIPSCs) seldom occurs in the absence of carbachol, a cholinergic agonist. The goal of this thesis is to identify the mechanism by which cholinergic stimulation facilitates DSI, using whole-cell, voltage-clamp recordings in CA1 pyramidal cells in the rat acute hippocampal slice preparation. Muscarinic, but not nicotinic, receptor activation increased the frequency and amplitude of sIPSCs and induced DSI. Pharmacological data suggest that M1 or M3 muscarinic receptors mediate this effect. Although cholinergic stimulation greatly facilitated DSI of sIPSCs, atropine-insensitive DSI occurred in the absence of carbachol, under certain circumstances (e.g., DSI of evoked IPSCs (eIPSCs)), suggesting that biochemical effectors activated by mAChR are not essential for induction of the DSI mechanism. Several lines of evidence suggest that carbachol facilitates DSI by increasing interneuronal activity. For example, DSI is not observed until large amplitude sIPSCs occur, and when the large amplitude sIPSCs are eliminated, DSI is no longer present. Norepinephrine and elevated extracellular potassium also increased sIPSC activity and induced DSI, which, in some cells, was comparable to that produced with carbachol. Moreover, baclofen, a GABA B receptor agonist which inhibits only a subset of IPSCs, reversibly blocked DSI of sIPSCs in carbachol, as well as DSI of eIPSCs in the presence of atropine. Therefore, DSI-susceptible IPSCs, whether activated by carbachol or electrical stimulation, originate from a subpopulation of interneurons possessing GABA B receptors. Additional experiments using localized electrical stimulation confirmed that only certain IPSCs are susceptible to DSI. We conclude that a subpopulation of interneurons, activated by cholinergic synaptic input, is particularly sensitive to DSI. Muscarinic receptor activation appears to facilitate DSI by increasing the occurrence of IPSCs susceptible to it.