Nicotinic receptor‐mediated enhancement of long‐term potentiation involves activation of metabotropic glutamate receptors and ryanodine‐sensitive calcium stores in the dentate gyrus

Abstract

Little is known about the mechanisms underlying the enhancement of long-term potentiation (LTP) by nicotine. In the present study, the mechanisms of nicotinic enhancement of LTP were investigated in the rat dentate gyrus in vitro. Acute application of nicotine enhanced LTP induction, an action requiring activation of alpha7 nicotinic acetylcholine receptors (nAChRs), as it was blocked by the nAChR antagonist methyl-lycaconitine, mimicked by the acetylcholine receptor agonist choline and absent in mutant mice null for alpha7 nAChR. Nicotinic enhancement of LTP was both dependent on N-methyl-D-aspartate receptor activation, as no LTP was induced in the presence of nicotine and an N-methyl-D-aspartate receptor antagonist, and expressed post-synaptically, as no change in paired-pulse ratio accompanied nicotinic enhancement of LTP. The nicotinic-enhanced component of LTP, unlike control LTP, was dependent on activation of metabotropic glutamate receptors (mGluRs), being inhibited by the group I/II antagonist LY341495 and the mGluR5 antagonist MPEP, and also dependent on influx of Ca via L-type Ca channels and release from ryanodine (RyR)-sensitive intracellular stores, being prevented by nifedipine and RyR, respectively. It is suggested that nicotinic activation of the Ca-permeable alpha7 nAChRs fills RyR Ca stores and release of Ca from such stores by high-frequency stimulation via Ca-induced Ca release and activation of mGluRs induces an additional component of LTP which summates with control LTP. Chronic application of nicotine in vivo also enhanced LTP induction in slices and was dependent on activation of mGluRs and Ca release from RyR-sensitive intracellular stores, although acutely applied nicotine was not required for such enhanced LTP.

Superoxide-Induced Potentiation in the Hippocampus Requires Activation of Ryanodine Receptor Type 3 and ERK

“…This suggests the presence of an additional calcium source upstream of RyR3 that is necessary for superoxide-induced potentiation. We investigated the contribution of L-type calcium channels because they have been shown to be a component of signaling cascades involving RyRs in both the dentate gyrus and cerebellum (Chavis et al 1996;Welsby et al 2006). Application of the L-type calcium channel blocker nifedipine (10 M) for half an hour before and during addition of X/XO blocked superoxide-induced potentiation (fEPSP slope ϭ 97 Ϯ 1.0% of baseline, n ϭ 6; Fig.…”

“…This effect was dependent on activation of L-type calcium channels but not NMDA receptors (Kamsler and Segal 2003). Furthermore, a functional coupling between RyRs and L-type calcium channels has been established in the dentate gyrus and cerebellar granule cells (Chavis et al 1996;Welsby et al 2006). Thus L-type channels may be an important calcium source upstream of RyRs that are required for the redox component of LTP.…”

Metabotropic glutamate receptor 5 as a potential target for smoking cessation

“…mGluR5s facilitate NMDAdependent long-term potentiation (LTP), as shown by several studies (for a review see Anwyl 2009). The fact that mGluR5 is involved in the phenomena of synaptic plasticity as LTP and longterm depression (LTD: Kawabata et al 1996;Jia et al 1998), provides an important pointer to its role in drug abuse-induced plasticity, including nicotine induced LTP (Welsby et al 2006). mGluR5 mRNA and protein expression studies reveal a pattern of receptor distribution of great relevance for neuropsychiatric disorders, including drug addiction.…”

D1/D5 receptors and histone deacetylation mediate the Gateway Effect of LTP in hippocampal dentate gyrus

“…Finally, the DG is a brain region that is highly sensitive to nicotine and significantly affects synaptic plasticity. Either application of nicotine in brain slices or subcutaneous injection of nicotine, in vivo, enhances LTP in dentate gyrus (Sawada et al 1994;Curran and Connor 2003;Welsby et al 2006Welsby et al , 2009. Acute nicotine treatment prevents sleep deprivation-induced impairment of LTP in the DG (Aleisa et al 2011) and administration of a highdose of nicotine causes synaptic potentiation in the DG, without pairing of tetanic stimulation (Matsuyama et al 2000;Tang and Dani 2009).…”