A dominant role for the beta 4 nicotinic receptor subunit in nicotinic modulation of glomerular microcircuits in the mouse olfactory bulb

Abstract

Nicotinic acetylcholine receptors (nAChRs) regulate information transfer across the main olfactory bulb by instituting a high-pass intensity filter allowing for the filtering out of weak inputs. Excitation-driven inhibition of the glomerular microcircuit via GABA release from periglomerular cells appears to underlie this effect of nAChR activation. The multiplicity of nAChR subtypes and cellular locations raises questions about their respective roles in mediating their effects on the glomerular output. In this study, we address this issue by targeting heteromeric nAChRs using receptor knockouts (KOs) for the two dominant nAChR β-subunit genes known to be expressed in the central nervous system. KOs of the β-nAChR subunit did not affect nAChR currents from mitral cells (MCs) but attenuated those from the external tufted (ET) cells. In slices from these animals, activation of nAChRs still effectively inhibited excitatory postsynaptic currents (EPSCs) and firing on MCs evoked by the olfactory nerve (ON) stimulation, thereby indicating that the filter mechanism was intact. On the other hand, recordings from β-KOs showed that nAChR responses from MCs were abolished and those from ET cells were attenuated. Excitation-driven feedback was abolished as was the effect of nAChR activation on ON-evoked EPSCs. Experiments using calcium imaging showed that one possible consequence of the β-subunit activation might be to alter the time course of calcium transients in juxtaglomerular neurons suggesting a role for these receptors in calcium signaling. Our results indicate that nAChRs containing the β-subunit are critical in the filtering of odor inputs and play a determinant role in the cholinergic modulation of glomerular output. NEW & NOTEWORTHY In this study, using receptor gene knockouts we examine the relative contributions of heteromeric nAChR subtypes located on different cell types to this effect of receptor activation. Our results demonstrate that nAChRs containing the β-subunit activate MCs resulting in feedback inhibition from glomerular interneurons. This period of inhibition results in the selective filtering of weak odor inputs providing one mechanism by which nAChRs can enhance discrimination between two closely related odors.

β4-Nicotinic Receptors Are Critically Involved in Reward-Related Behaviors and Self-Regulation of Nicotine Reinforcement

“…Several brain areas that express b4 could account for this difference. For instance b4*nAChR are present in olfactory and taste circuits (Qian et al, 2018;Spindle et al, 2018). Also viral knockdown of the b4 subunit in hypothalamic proopiomelanocortin neurons blocked the anorexigenic effect of cytisine, a selective agonist of a3b4 nAChRs (Mineur et al, 2011;Calarco et al, 2018).…”

Circuit formation and sensory perception in the mouse olfactory system

“…In addition to the BF GABAergic cells, cholinergic cells in the horizontal limb of the diagonal band of the BF densely innervate the glomerular circuits (Zaborszky et al, 1986;Bendahmane et al, 2016). While the BF GABAergic inhibitory axons target only Type 2 PGCs, the BF cholinergic axons target apical dendrites of all types of projection neurons including eTCs and Type 2.3 PGCs (a subset of Type 2 PGCs) (Spindle et al, 2018;De Saint Jan, 2022) (Figure 1D). BF cholinergic cells are tonically active during wakefulness but silent during slow-wave sleep (Xu et al, 2015).…”