Nicotinic receptors modulate olfactory bulb external tufted cells via an excitation-dependent inhibitory mechanism

Abstract

Olfactory bulb (OB) glomeruli, the initial sites of synaptic processing of odor information, exhibit high levels of nicotinic acetylcholine receptor (nAChR) expression and receive strong cholinergic input from the basal forebrain. The role of glomerular nAChRs in olfactory processing, however, remains to be elucidated. External tufted (ET) cells are a major source of excitation in the glomerulus and an important component of OB physiology. We have examined the role of nAChRs in modulating ET cell activity using whole-cell electrophysiology in mouse OB slices. We show here that the activation of glomerular nAChRs leads to direct ET cell excitation, as well as an increase in the frequency of spontaneous postsynaptic GABAergic currents. β2-containing nAChRs, likely the α4β2*-nAChR subtype (* represents the possible presence of other subunits), were significant contributors to these effects. The nAChR-mediated increase in spontaneous postsynaptic GABAergic current frequency on ET cells was, for the most part, dependent on glutamate receptor activation, thus implicating a role for excitation-dependent inhibition within the glomerulus. β2-containing nAChRs also regulate the frequency of miniature inhibitory postsynaptic currents on ET cells, implying nicotinic modulation of dendrodendritic signaling between ET and periglomerular cells. Our data also indicate that nAChR activation does not affect spontaneous or evoked transmission at the olfactory nerve-to-ET cell synapse. The results from this study suggest that ET cells, along with mitral cells, play an important role in the nicotinic modulation of glomerular inhibition.

Signaling between periglomerular cells reveals a bimodal role for GABA in modulating glomerular microcircuitry in the olfactory bulb

“…Calcium transients in response to 1 mM ACh/At were recorded from JG neurons from slices loaded with fura-2AM. Consistent with the data presented above and previous laboratory work (10,19), activation of nAChRs produced robust calcium transients that were blocked on incubation with 5 μM Mec (86 ± 5.6% block; n = 35 cells; P < 10 −5 , paired t test) (Fig. 4E).…”

“…4C). This is similar to the data obtained on nAChR-mediated increases in sGPSC frequencies on MCs and ET cells (10,19) and suggests that the GABAergic signaling in these neurons in the glomerular microcircuit is secondary to excitation and glutamate release, presumably from nAChRmediated activation of MCs and ET cells.…”

“…(F) A model for GIGR. Functional nAChRs (red crescents) are expressed on MC primary dendrites and on ET cells (10,19). Release of ACh from basal forebrain cholinergic neurons (red; 1) activates the nAChRs, resulting in glutamate release onto a population of PG cells (green; 2).…”

“…Although dendrodendritic signaling between PG cells has been demonstrated (8,9), the context in which these synapses are activated remains unclear. In previous work, we showed that activation of nAChRs in the glomerulus elicits excitation-dependent GABA release from PG cells, leading to the filtering out of MC responses to low-intensity stimuli while maintaining effective information transfer at high stimulus intensities (10,18,19).…”

Functional differentiation of cholinergic and noradrenergic modulation in a biophysical model of olfactory bulb granule cells

“…MCs in the microcircuit simulations serve as a reasonably realistic assay for the effects of GC neuromodulation on GC functional output, but the direct neuromodulation of MCs was not simulated. Specifically, besides the muscarinic effects on GCs, ACh directly depolarizes MCs via nicotinic receptors (Castillo et al 1999;D'Souza and Vijayaraghavan 2012;Liu et al 2015) and also enhances the glomerular layer inhibition of MCs through both nicotinic and muscarinic receptors (Castillo et al 1999;D'Souza and Vijayaraghavan 2012;D'Souza et al 2013;Liu et al 2015). Although not simulated in the present MC-GC microcircuit model, many of these effects have been integrated and examined in a previous OB network model (Li and Cleland 2013).…”