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

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Abstract
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 α7 gene product and has a high relative permeability to calcium. Both on rodent hippocampal interneurons and on chick ciliary ganglion neurons these α7‐nAChRs are often closely juxtaposed to GABAA receptors. We show here that in both cases activation of α7‐nAChRs on the postsynaptic neuron acutely down‐regulates GABA‐induced currents. Nicotine application to dissociated ciliary ganglion neurons diminished subsequent GABAA receptor responses to GABA. The effect was blocked by α7‐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 GABAA 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 α7‐nAChR knockout mice. Moreover, α7‐nAChR blockade in hippocampal slices reduced rundown of GABAA receptor‐mediated whole‐cell responses, indicating ongoing endogenous modulation. The results demonstrate regulation of GABAA receptors by α7‐nAChRs on the postsynaptic neuron and identify a new mechanism by which nicotinic cholinergic signalling influences nervous system function.

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