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.

Low-voltage-activated (LVA) Ca2+ channels are widely distributed throughout the CNS and are important determinants of neuronal excitability, initiating dendritic and somatic Ca2+ spikes that trigger and shape the pattern of action potential firing. Here, we define a molecular mechanism underlying the dynamic regulation of alpha1H channels (Cav3.2), by Ca2+/CaM-dependent protein kinase II (CaMKII). We show that channel regulation is selective for the LVA alpha1H Ca2+ channel subtype, depends on determinants in the alpha1H II-III intracellular loop, and requires the phosphorylation of a serine residue absent from unregulated alpha1G (Cav3.1) channels. These studies identify the alpha1H channel as a new substrate for CaMKII and provide the first molecular mechanism for the direct regulation of T-type Ca2+ channels by a protein kinase. Our data suggest a novel mechanism for modulating the integrative properties of neurons.

(2009) Intracellular mechanisms underlying the nicotinic enhancement of LTP in the rat dentate gyrus. European Journal of Neuroscience, 29 (1). pp. 6575. ISSN 0953816XIt is advisable to refer to the publisher's version if you intend to cite from the work.http://dx.doi.org/10.1111/j. 1460-9568.2008.06562.x For more information about UCLan's research in this area go to http://www.uclan.ac.uk/researchgroups/ and search for . AbstractWe have previously shown that activation of nicotinic acetylcholine receptors enhanced long-term potentiation (LTP) in the rat dentate gyrus in vitro via activation of α7 nicotinic acetylcholine receptor (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

No abstract