Intracellular mechanisms underlying the nicotinic enhancement of LTP in the rat dentate gyrus.
We have previously shown that activation of nicotinic acetylcholine receptors (nAChRs) enhanced long-term potentiation (LTP) in the rat dentate gyrus in vitro via activation of alpha7 nAChR. In the present studies, mechanisms underlying the acute and chronic nicotinic enhancement of LTP were examined. In particular, the involvement of activation of intracellular kinases was examined using selective kinase antagonists, and the effects of enhancing cholinergic function with positive allosteric modulators of the alpha7 nAChR and with acetylcholinesterase (AChE) inhibitors were also investigated. Activation of extracellular signal-regulated kinase (ERK) and cAMP-dependent protein kinase (PKA) was found to be involved in the induction of the acute nicotinic enhancement of LTP, although not control LTP. In contrast, activation of the tyrosine kinase Src, Ca(2+)-calmodulin-dependent protein kinase II, Janus kinase 2 and p38 mitogen-activated protein kinase was not involved in the acute nicotinic enhancement of LTP, although Src activation was necessary for control LTP. Moreover, activation of phosphoinositide 3-kinase was involved in the acute nicotinic enhancement of LTP to a much lesser extent than in control LTP. Chronic nicotine enhancement of LTP was found to be dependent on PKA, ERK and Src kinases. Acute nicotinic enhancement of LTP was occluded by chronic nicotine treatment. The positive allosteric modulator PNU-120596 was found to strongly reduce the threshold for nicotinic enhancement of LTP, an affect mediated via the alpha7 nAChR as it was blocked by the selective antagonist methyllycaconitine. The AChE inhibitors tacrine and physostigmine enhanced control LTP.
Welsby
Philip J
PJ
Department of Pharmacology and Therapeutics, National University of Ireland, Galway, Ireland. philip.welsby@nuigalway.ie
Rowan
Michael J
MJ
Anwyl
Roger
R
D000109:Acetylcholine / Q000378:metabolism*; D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism*; D007555:Isoxazoles / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D009924:Organ Culture Techniques; D010671:Phenylurea Compounds / Q000494:pharmacology; D010770:Phosphotransferases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D064569:alpha7 Nicotinic Acetylcholine Receptor; D019061:src-Family Kinases / Q000187:drug effects / Q000378:metabolism
C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; D002800:Cholinesterase Inhibitors; C579165:Chrna7 protein, rat; D007555:Isoxazoles; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D010671:Phenylurea Compounds; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D010770:Phosphotransferases; D019061:src-Family Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D000109:Acetylcholine