Regulation of the activity of hippocampal stratum oriens interneurons by alpha7 nicotinic acetylcholine receptors.
GABAergic interneurons have been shown to be a major target of cholinergic inputs to the hippocampus. Because these interneurons project to pyramidal neurons as well as other interneurons, activation of the cholinergic system is likely to produce a complex modulation of local inhibitory activity. To better understand the role of post-synaptic alpha7 nicotinic acetylcholine receptors in the hippocampus, we have characterized the effects of nicotinic agents on local interneurons of the rat CA1 stratum oriens in terms of activation, desensitization, and region of axonal termination. Fast application of acetylcholine onto stratum oriens interneurons during whole-cell recordings from hippocampal slices activated the majority of cells tested, and these responses were mediated almost entirely by alpha7 nicotinic acetylcholine receptors. Anatomical reconstructions showed no clear relationship between the acetylcholine responsivity of interneurons and the regions to which their axons project. Currents mediated by alpha7 receptors declined markedly during repetitive activation in the theta rhythm range (4-12 Hz) when activated by either pressure application or synaptic release of acetylcholine. However, the decay of alpha7 receptor-mediated currents was unaffected by treatment with the cholinesterase inhibitor neostigmine (10 nM-10 microM), suggesting that hydrolysis of acetylcholine is not a rate-limiting step in the termination of these responses. From these findings we suggest that nicotinic receptor activity in this region has an extensive and complex impact on local inhibitory circuits that is mediated by activation of several classes of intrinsic GABAergic cells. In addition, desensitization of the alpha7 nicotinic acetylcholine receptor is likely to contribute to the decay of individual responses to pressure application of agonist, and may also act in a cumulative fashion to impair the ability of these receptors to support repetitive activity during trains of activation. If applicable to alpha7 receptor responses in vivo, we suggest it may be difficult to enhance these responses for therapeutic purposes with cholinesterase inhibitors.
Buhler
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Department of Pharmacology, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Denver, CO 80262, USA. amber-buhler@uiowa.edu
Dunwiddie
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TV
D000109:Acetylcholine / Q000378:metabolism* / Q000494:pharmacology; D000110:Acetylcholinesterase / Q000187:drug effects / Q000378:metabolism; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007395:Interneurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008239:Lysine / Q000031:analogs & derivatives* / Q000378:metabolism; D008297:Male; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D058919:Purinergic P2 Receptor Antagonists; D017966:Pyramidal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013826:Theta Rhythm / Q000187:drug effects; D064569:alpha7 Nicotinic Acetylcholine Receptor; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D002800:Cholinesterase Inhibitors; C579165:Chrna7 protein, rat; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D058919:Purinergic P2 Receptor Antagonists; D011978:Receptors, Nicotinic; D018048:Receptors, Purinergic P2; D012702:Serotonin Antagonists; D064569:alpha7 Nicotinic Acetylcholine Receptor; D005680:gamma-Aminobutyric Acid; D000110:Acetylcholinesterase; C013411:biocytin; D008239:Lysine; D000109:Acetylcholine