Abstract
Presynaptic nicotinic acetylcholine receptors (nAChRs) have long been implicated in the modulation of CNS circuits. We previously reported that brief exposure to low concentrations of nicotine induced sustained potentiation of glutamatergic transmission at ventral hippocampal (vHipp)-striatal synapses. Here, we exploited nAChR subtype-selective antagonists and agonists and α7*nAChR knockout mutant mice (α7-/-) to elucidate the signaling mechanisms underlying nAChR-mediated modulation of synaptic transmission. Using a combination of micro-slices culture from WT and α7-/-mice, calcium imaging, and immuno-histochemical techniques, we found that nicotine elicits localized and oscillatory increases in intracellular Ca2+ along vHipp axons that persists for up to 30 minutes. The sustained phase of the nicotine-induced Ca2+ response was blocked by α-BgTx but not by DHβE and was mimicked by α7*nAChR agonists but not by non-α7*nAChR agonists. In vHipp slices from α7-/- mice, nicotine elicited only transient increases of axonal Ca2+ signals and did not activate CaMKII. The sustained phase of the nicotine-induced Ca2+ response required localized activation of CaMKII, phospholipase C, and IP3 receptor mediated Ca2+-induced Ca2+ release (CICR). In conclusion, activation of presynaptic nAChRs by nicotine elicits Ca2+ influx into the presynaptic axons, the sustained phase of the nicotine-induced Ca2+ response requires that axonal α7*nAChR activate a downstream signaling network in the vHipp axons.
Highlights
Neuronal nicotinic acetylcholine receptors influence the excitability of circuits that underlie fundamental aspects of behaviors related to memory, motivation and mood [1,2,3,4,5,6]
We developed a specialized preparation of hippocampal– striatalcircuits in vitro to examine the cellular signaling mechanisms by which presynaptic nicotinic acetylcholine receptors (nAChRs) modulate synaptic transmission
We previously demonstrated that nicotine elicits a sustained (>30min) potentiation of glutamatergic transmission via activation of α7*nAChRs [33]
Summary
Neuronal nicotinic acetylcholine receptors (nAChRs) influence the excitability of circuits that underlie fundamental aspects of behaviors related to memory, motivation and mood [1,2,3,4,5,6]. Neuronal nAChRs have been proposed as potential therapeutic targets for cognitive dysfunctions associated with Alzheimer’s disease and schizophrenia [13,14,15]. Previous studies have shown that (α4β2)* and α7* nAChRs are localized in various cellular domains, including cell bodies, presynaptic terminals, post- and peri-synaptic sites [19,20,21]. Electrophysiological, immunochemical and pharmacological evidence support the presence of (α4β2)* and α7*nAChRs on presynaptic glutamatergic axon terminals, where they modulate the strength of glutamatergic neurotransmission [19,22,23,24,25]. Modulation of the release of neurotransmitters (including glutamate, GABA, ACh, and dopamine) by activation of presynaptic nAChRs is the most prevalent mechanism of nicotinic facilitation of synaptic transmission in the CNS [22,23,26,27]. Nicotinic modulation of circuit excitability by activation of presynaptic nAChRs is critical to CNS function [28,29,30,31,32], the mechanisms by which nAChR activation leads to long-term changes in presynaptic function are not known
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