Received for publication April 18, 2006.
Revised July 7, 2006.
Accepted for publication July 7, 2006.

The magnitude of 7 nicotinic receptor currents in rat hippocampal neurons is dependent upon GABAergic activity and depolarization

Abstract

Hippocampal alpha7* 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 affect the function of alpha7*. The amplitude of alpha7*-gated whole-cell currents in cultured rat hippocampal neurons exposed to high extracellular K⁺ (KCl 40 mM) for 24-48 h increased 1.3 to 5.5 times. The proportion of alpha7*-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 alpha7* responses were seen after 24-h blockade of N-type calcium channels, but not of L-type calcium channels, NMDA or non-NMDA receptor channels, protein kinase C, or calcium-calmodulin kinases II/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 alpha7*-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.

Key words: acetylcholine, alpha7, calcium, epilepsy, nicotinic receptors, up-regulation