Nicotinic and muscarinic agonists and acetylcholinesterase inhibitors stimulate a common pathway to enhance GluN2B-NMDAR responses

Abstract

Nicotinic and muscarinic ACh receptor agonists and acetylcholinesterase inhibitors (AChEIs) can enhance cognitive function. However, it is unknown whether a common signaling pathway is involved in the effect. Here, we show that in vivo administration of nicotine, AChEIs, and an m1 muscarinic (m1) agonist increase glutamate receptor, ionotropic, N-methyl D-aspartate 2B (GluN2B)-containing NMDA receptor (NR2B-NMDAR) responses, a necessary component in memory formation, in hippocampal CA1 pyramidal cells, and that coadministration of the m1 antagonist pirenzepine prevents the effect of cholinergic drugs. These observations suggest that the effect of nicotine is secondary to increased release of ACh via the activation of nicotinic ACh receptors (nAChRs) and involves m1 receptor activation through ACh. In vitro activation of m1 receptors causes the selective enhancement of NR2B-NMDAR responses in CA1 pyramidal cells, and in vivo exposure to cholinergic drugs occludes the in vitro effect. Furthermore, in vivo exposure to cholinergic drugs suppresses the potentiating effect of Src on NMDAR responses in vitro. These results suggest that exposure to cholinergic drugs maximally stimulates the m1/guanine nucleotide-binding protein subunit alpha q/PKC/proline-rich tyrosine kinase 2/Src signaling pathway for the potentiation of NMDAR responses in vivo, occluding the in vitro effects of m1 activation and Src. Thus, our results indicate not only that nAChRs, ACh, and m1 receptors are on the same pathway involving Src signaling but also that NR2B-NMDARs are a point of convergence of cholinergic and glutamatergic pathways involved in learning and memory. m1 muscarinic receptor | donepezil | hippocampus N icotinic and muscarinic agonists can produce cognitive enhancement (1, 2). Acetylcholinesterase inhibitors (AChEIs) also cause cognitive enhancement by increasing ACh levels (3, 4). However, it is largely unknown whether the effect of ACh is mediated by nicotinic ACh receptors (nAChRs), muscarinic receptors, or both. Studies involving cholinergic lesions and local administration of cholinergic antagonists indicate that both nAChRs and muscarinic receptors located in the hippocampus are of particular importance for learning and memory processes (5-8). However, the mechanisms by which these receptors mediate cognitive enhancement largely remain to be elucidated.Synaptic plasticity is thought to be a critical component underlying learning and memory (9, 10), and the NMDA receptor (NMDAR) is a key component of synaptic plasticity (9, 11). Thus, studies of the modulation of NMDAR responses and longterm potentiation (LTP) induction by cholinergic drugs (12)(13)(14)(15)(16)(17)(18)(19)(20) help elucidate the mechanisms of cholinergic facilitation of learning and memory. In vitro acute nicotine can potentiate NMDAR-mediated responses in CA1 pyramidal cells in hippocampal slices via at least two different mechanisms (16,18). One of these mechanisms is absent after a selective cholinergic lesion (21) and is paradoxically blocked by the mu...

Early postnatal nicotine exposure causes hippocampus-dependent memory impairments in adolescent mice: Association with altered nicotinic cholinergic modulation of LTP, but not impaired LTP

“…Thus, these findings demonstrate the significance of nAChR activity during early brain development, and indicate the critical role of timing-dependent cholinergic induction of synaptic plasticity (Gu et al , 2012; Gu and Yakel, 2011; Ji et al , 2001) and other nicotinic cholinergic-dependent mechanisms of synaptic plasticity (Halff et al , 2014; Ishibashi et al , 2014; Nakauchi and Sumikawa, 2012; Yamazaki et al , 2006) in spatial memory.…”

Nicotine-induced neuroplasticity counteracts the effect of schizophrenia-linked neuregulin 1 signaling on NMDAR function in the rat hippocampus

“…The current study was designed based on our previous results demonstrating that chronic nicotine exposure in Sprague-Dawley rat pups (starting at around postnatal day 21) by subcutaneous injection of nicotine (0.5–1 mg/kg nicotine base, twice daily for 10 to 15 days) causes the enhancement of NMDAR-mediated responses via Src upregulation in adolescence (Yamazaki et al, 2006a, b; Ishibashi et al, 2014). Therefore, to achieve the same effect of nicotine in adolescence, the same treatment regimen was used in the present study.…”

“…Nicotine injection induced seizures in most of the pups, which were usually brief, and the effect of nicotine became progressively weaker by continuing daily injection of nicotine. Nicotine-induced enhancement of NMDAR-mediated responses was mimicked by a muscarinic ACh receptor agonist and acetylcholinesterase inhibitors without inducing seizures, and co-administration of the m1 antagonist pirenzepine prevents the effect of nicotine without blocking nicotine-induced seizures (Ishibashi et al, 2014). These observations suggest that the effect of nicotine is mediated by increased release of ACh via the activation of nicotinic acetylcholine receptors (nAChRs) and involves m1 muscarinic receptor activation through ACh, but not nicotine-induced seizures.…”

“…Interestingly, this effect of nicotine is mimicked by two acetylcholinesterase inhibitors, donepezil and galantamine (Ishibashi et al, 2014), which are currently used for treatment of cognitive deficits associated with Alzheimer’s disease (AD). Furthermore, administration of these cholinergic drugs has also been shown to improve cognition in schizophrenic patients (Levin et al, 2006; Gray and Roth, 2007; Buchanan et al, 2008).…”

Perceptual inference

“…Acetylcholine (ACh) has been hypothesised to be necessary for top-down attentional modulation (Deco and Thiele, 2011). ACh affects synaptic transmission through NMDA receptors (FloresHernandez et al, 2009;Ishibashi et al, 2014;Zappettini et al, 2014;Salamone et al, 2014;Zhang et al, 2014) and may, therefore, be partially responsible for NMDA receptor dependent synaptic plasticity. Indeed, reinforcement learning has been proposed as a key component in the development of perceptual and more generally causal inference (Shams and Beierholm, 2010).…”