Reversible inhibition of GABAA receptors by alpha7-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 alpha7 gene product and has a high relative permeability to calcium. Both on rodent hippocampal interneurons and on chick ciliary ganglion neurons these alpha7-nAChRs are often closely juxtaposed to GABAA receptors. We show here that in both cases activation of alpha7-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 alpha7-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 alpha7-nAChR knockout mice. Moreover, alpha7-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 alpha7-nAChRs on the postsynaptic neuron and identify a new mechanism by which nicotinic cholinergic signalling influences nervous system function.
Zhang
Jingming
J
Neurobiology Section, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Berg
Darwin K
DK
D000818:Animals; D018929:Cell Culture Techniques; D002642:Chick Embryo; D002645:Chickens; D002799:Cholinergic Fibers / Q000502:physiology; D005260:Female; D005726:Ganglia, Parasympathetic / Q000166:cytology / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology; D007395:Interneurons / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009433:Neural Inhibition / Q000502:physiology; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D011963:Receptors, GABA-A / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000502:physiology; D064569:alpha7 Nicotinic Acetylcholine Receptor; D005680:gamma-Aminobutyric Acid / Q000502:physiology
C579166:Chrna7 protein, mouse; D011963:Receptors, GABA-A; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D005680:gamma-Aminobutyric Acid