Nicotinic α7 receptor activation selectively potentiates the function of NMDA receptors in glutamatergic terminals of the nucleus accumbens

Abstract

We here provide functional and immunocytochemical evidence supporting the co-localization and functional interaction between nicotinic acetylcholine receptors (nAChRs) and N-methyl-D-aspartic acid receptors (NMDARs) in glutamatergic terminals of the nucleus accumbens (NAc). Immunocytochemical studies showed that a significant percentage of NAc terminals were glutamatergic and possessed GluN1 and α7-containing nAChR. A short-term pre-exposure of synaptosomes to nicotine (30 µM) or choline (1 mM) caused a significant potentiation of the 100 µM NMDA-evoked [3H]D-aspartate ([3H]D-Asp) outflow, which was prevented by α-bungarotoxin (100 nM). The pre-exposure to nicotine (100 µM) or choline (1 mM) also enhanced the NMDA-induced cytosolic free calcium levels, as measured by FURA-2 fluorescence imaging in individual NAc terminals, an effect also prevented by α-bungarotoxin. Pre-exposure to the α4-nAChR agonists 5IA85380 (10 nM) or RJR2429 (1 µM) did not modify NMDA-evoked ([3H]D-Asp) outflow and calcium transients. The NMDA-evoked ([3H]D-Asp) overflow was partially antagonized by the NMDAR antagonists MK801, D-AP5, 5,7-DCKA and R(-)CPP and unaffected by the GluN2B-NMDAR antagonists Ro256981 and ifenprodil. Notably, pre-treatment with choline increased GluN2A biotin-tagged proteins. In conclusion, our results show that the GluN2A-NMDA receptor function can be positively regulated in NAc terminals in response to a brief incubation with α7 but not α4 nAChRs agonists. This might be a general feature in different brain areas since a similar nAChR-mediated bolstering of NMDA-induced ([3H]D-Asp) overflow was also observed in hippocampal synaptosomes.

Septal Cholinergic Neuromodulation Tunes the Astrocyte-Dependent Gating of Hippocampal NMDA Receptors to Wakefulness

“…The most abundant nAChRs expressed by hippocampal astrocytes in C57Bl/6 mice are α4β2- and α4β4-nAChRs (Gahring et al, 2004) but Carba still caused a full saturation of NMDARs in the presence the α4β4- and α4β2-nAChR antagonist DHβE (P = 0.889). In contrast, we found that the effect of Carba was prevented by the α7nAChR antagonist MLA (Figure 5A, P < 10 −9 ), in line with observations that α7nAChR activation promotes NMDAR activity (Lin et al, 2013; Yang et al, 2013; Zappettini et al, 2014) and favors D-serine release (Singh et al, 2013). As expected from this finding, the α7nAChR selective agonist AR-R17779 (AR-R) alone elicited a full saturation of NMDARs (P < 10 −8 vs control), which was attenuated by the co-application of MLA (P < 10 −4 vs AR-R).…”

“…In addition to being tightly correlated with vigilance states (Lee et al, 2005; Marrosu et al, 1995; Zant et al, 2016), cholinergic signaling potentiates NMDAR activity and modulates NMDAR-dependent functions (Kirkwood et al, 1999; Lin et al, 2013; Markram and Segal, 1990; Yang et al, 2013; Zappettini et al, 2014). ACh also elicits intracellular Ca 2+ signaling in astrocytes through muscarinic receptors (Takata et al, 2011), α4β2- and α4β4-nAChRs receptors (Gahring et al, 2004), or α7nAChRs (Sharma and Vijayaraghavan, 2001; Shen and Yakel, 2012) and can promote D-serine release or synthesis (Lin et al, 2013; Singh et al, 2013; Takata et al, 2011).…”

“…In these regions, the ACh tone fluctuates with changes in vigilance state: the highest levels are found during active wakefulness and the lowest during slow wave sleep (Marrosu et al, 1995; Lee et al, 2005; Zant et al, 2016). Interestingly, ACh is known to influence NMDAR activity and NMDAR-dependent functions (Kirkwood et al, 1999; Lin et al, 2013; Markram and Segal, 1990; Yang et al, 2013; Zappettini et al, 2014), and activates intracellular signaling in astrocytes through various ACh receptors (AChRs) (Hirase et al, 2014; Sharma and Vijayaraghavan, 2001; Shen and Yakel, 2012; Takata et al, 2011). Combined with evidence that ACh can promote D-serine synthesis and/or release (Lin et al, 2013; Singh et al, 2013; Takata et al, 2011), these data point to a link between vigilance state-dependent cholinergic activity and NMDAR co-agonist gating via astrocytic D-serine.…”

Modulation of excitatory neurotransmission by neuronal/glial signalling molecules: interplay between purinergic and glutamatergic systems

“…In contrast, nicotine has been reported to evoke internalization of presynaptic NMDA receptors in dopaminergic terminals of the rat nucleus accumbens resulting in decreased NMDA-induced dopamine release [147]. On the other hand, nicotine pretreatment increased the responses of the NMDA receptors, which contain the GluN2A subunits, via activation of α7-nACh receptor subtypes on the glutamatergic nerve endings of the nucleus accumbens [148].…”

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).…”