The magnitude of α7 nicotinic receptor currents in rat hippocampal neurons is dependent upon GABAergic activity and depolarization

Hippocampal alpha 7* nicotinic acetylcholine receptors modulate the release of GABA and glutamate. The control of functional receptor pools by cell firing or synaptic activity could therefore allow for a local adjustment of the sensitivity to cholinergic input upon changes in neuronal activity. We first investigated whether tonic depolarization or cell firing affected the function of alpha 7*. The amplitude of alpha 7*-gated whole-cell currents in cultured rat hippocampal neurons exposed to high-extracellular K+ (40 mM KCl) for 24 to 48 h increased 1.3 to 5.5 times. The proportion of alpha 7*- responsive neurons (99%), the potency of acetylcholine, and the sensitivity to nicotinic antagonists were all unaffected. In contrast, block of spontaneous cell firing with tetrodotoxin for 24 h led to a 37% reduction in mean current amplitude. Reduced alpha 7* responses were seen after a 24-h blockade of N-type calcium channels but not of L-type calcium channels, N-methyl-D-aspartate (NMDA), or non-NMDA receptor channels, protein kinase C, or calcium-calmodulin kinases II and IV. The N-type or L-type calcium channel antagonists omega-conotoxin GVIA and nifedipine did not prevent the current-potentiating effect of KCl. The GABA(A) antagonist picrotoxin led to a 44% reduction of the currents, despite increasing action potential firing, and also reversed the potentiating effect of KCl. Treatment with GABA, midazolam, or a GABA uptake blocker led to increased currents. These data indicate that alpha 7*-gated currents in hippocampal neurons are regulated by GABAergic activity and suggest that depolarization- induced GABA release may underlie the effect of increased extracellular KCl.