Reversible inhibition of GABAA receptors by α7-containing nicotinic receptors on the vertebrate postsynaptic neurons

Nicotinic acetylcholine receptors (nAChRs) are expressed throughout the central nervous system and influence a variety of higher order functions including learning and memory. While the effects of presynaptic nAChRs on transmitter release have been well documented, little is known about possible postsynaptic actions. A major species of neuronal nAChRs contains the alpha 7 gene product and has a high relative permeability to calcium. Both on rodent hippocampal interneurons and on chick ciliary ganglion neurons these alpha 7-nAChRs are often closely juxtaposed to GABA(A) receptors. We show here that in both cases activation of alpha 7-nAChRs on the postsynaptic neuron acutely down-regulates GABA-induced currents. Nicotine application to dissociated ciliary ganglion neurons diminished subsequent GABA(A) receptor responses to GABA. The effect was blocked by alpha 7-nAChR antagonists, by chelation of intracellular Ca2+ with BAPTA, and by inhibition of both Ca2+-calmodulin-dependent protein kinase II and mitogen-activated protein kinase. A similar outcome was obtained in the hippocampus where electrical stimulation to activate cholinergic fibres reduced the amplitude of subsequent GABA(A) receptor-mediated inhibitory postsynaptic currents. The reduction showed the same calcium and kinase dependence seen in ciliary ganglion neurons and was absent in hippocampal slices from alpha 7-nAChR knockout mice. Moreover, alpha 7-nAChR blockade in hippocampal slices reduced rundown of GABA(A) receptor-mediated whole-cell responses, indicating ongoing endogenous modulation. The results demonstrate regulation of GABA(A) receptors by alpha 7-nAChRs on the postsynaptic neuron and identify a new mechanism by which nicotinic cholinergic signalling influences nervous system function.