Activation of α7 nicotinic acetylcholine receptors persistently enhances hippocampal synaptic transmission and prevents Aß-mediated inhibition of LTP in the rat hippocampus.
Nicotinic acetylcholine receptors mediate fast cholinergic modulation of glutamatergic transmission and synaptic plasticity. Here we investigated the effects of subtype selective activation of the α7 nicotinic acetylcholine receptors on hippocampal transmission and the inhibition of synaptic long-term potentiation by the Alzheimer's disease associated amyloid ß-protein (Aß). The α7 nicotinic acetylcholine receptor agonist "compound A" ((R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl))thiophene-2-carboxamide) induced a rapid-onset persistent enhancement of synaptic transmission in the dentate gyrus in vitro. Consistent with a requirement for activation of α7 nicotinic acetylcholine receptors, the type II α7-selective positive allosteric modulator PheTQS ((3aR, 4S, 9bS)-4-(4-methylphenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide) potentiated, and the antagonist methyllycaconitine (MLA) prevented the persistent enhancement. Systemic injection of the agonist also induced a similar MLA-sensitive persistent enhancement of synaptic transmission in the CA1 area in vivo. Remarkably, although compound A did not affect control long-term potentiation (LTP) in vitro, it prevented the inhibition of LTP by Aß1-42 and this effect was inhibited by MLA. These findings strongly indicate that activation of α7 nicotinic acetylcholine receptors is sufficient to persistently enhance hippocampal synaptic transmission and to overcome the inhibition of LTP by Aß.
Department of Pharmacology and Therapeutics, Trinity College Dublin, Dublin 2, Ireland.
Tomas
T
Ondrejcak
Qinwen
Q
Wang
James N C
JN
Kew
David J
DJ
Virley
Neil
N
Upton
Roger
R
Anwyl
Michael J
MJ
Rowan
D000494:Allosteric Regulation / Q000187:drug effects; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D004347:Drug Interactions; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D018722:Nicotinic Agonists / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects*; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor
D016229:Amyloid beta-Peptides; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; D013449:Sulfonamides; D013876:Thiophenes; D064569:alpha7 Nicotinic Acetylcholine Receptor; C075222:amyloid beta-protein (1-42)