Muscarinic Receptors Modulate Dendrodendritic Inhibitory Synapses to Sculpt Glomerular Output

Abstract

Cholinergic [acetylcholine (ACh)] axons from the basal forebrain innervate olfactory bulb glomeruli, the initial site of synaptic integration in the olfactory system. Both nicotinic acetylcholine receptors (nAChRs) and muscarinic acetylcholine receptors (mAChRs) are expressed in glomeruli. The activation of nAChRs directly excites both mitral/tufted cells (MTCs) and external tufted cells (ETCs), the two major excitatory neurons that transmit glomerular output. The functional roles of mAChRs in glomerular circuits are unknown. We show that the restricted glomerular application of ACh causes rapid, brief nAChR-mediated excitation of both MTCs and ETCs in the mouse olfactory bulb. This excitation is followed by mAChR-mediated inhibition, which is blocked by GABA A receptor antagonists, indicating the engagement of periglomerular cells (PGCs) and/or short axon cells (SACs), the two major glomerular inhibitory neurons. Indeed, selective activation of glomerular mAChRs, with ionotropic GluRs and nAChRs blocked, increased IPSCs in MTCs and ETCs, indicating that mAChRs recruit glomerular inhibitory circuits. Selective activation of glomerular mAChRs in the presence of tetrodotoxin increased IPSCs in all glomerular neurons, indicating action potential-independent enhancement of GABA release from PGC and/or SAC dendrodendritic synapses. mAChR-mediated enhancement of GABA release also presynaptically suppressed the first synapse of the olfactory system via GABA B receptors on sensory terminals. Together, these results indicate that cholinergic modulation of glomerular circuits is biphasic, involving an initial excitation of MTC/ETCs mediated by nAChRs followed by inhibition mediated directly by mAChRs on PGCs/SACs. This may phasically enhance the sensitivity of glomerular outputs to odorants, an action that is consistent with recent in vivo findings.

Serotonin increases synaptic activity in olfactory bulb glomeruli

“…A striking feature of OB circuitry is the prominence of dendrodendritic synapses in addition to classical axodendritic synapses (Hinds 1970;Pinching and Powell 1971a,b;White 1973;Kasowski et al 1999;Kosaka and Kosaka 2011). Dendrodendritic synapses can support action potential-independent neurotransmission between MCs and granule cells (Jahr and Nicoll 1980;Shepherd 1998) and among neurons in the glomerular layer (Aroniadou-Anderjaska et al 1999;Murphy et al 2005;Masurkar and Chen 2012;D'Souza et al 2013;Fekete et al 2014;Liu et al 2015;Parsa et al 2015).…”

“…Acetylcholine, another modulatory transmitter, evokes action potential-independent GABA release from dendrodendritic synapses formed by granule cells (Castillo et al 1999;Ghatpande et al 2006;Pressler et al 2007) and glomerular interneurons (D'Souza et al 2013;Liu et al 2015). Thus two different modulatory neurotransmitters, ACh and 5HT, increase release probability from OB dendrodendritic synapses, suggesting that these synaptic arrangements may be important targets of neuromodulators in the OB.…”

“…Many OB interneurons, including SACs and PGCs form circuits through dendrodendritic synapses (Hinds 1970;Jahr and Nicoll 1982;Masurkar and Chen 2012;D'Souza et al 2013). Thus dendrodendritic synapses are potential targets of 5HT neuromodulation (D'Souza et al 2013;Liu et al 2015).…”

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).…”

Internal Cholinergic Regulation of Learning and Recall in a Model of Olfactory Processing

“…In the OB, Ach has been shown to modulate principal cells and different classes of interneurons via both nicotinic and muscarinic receptors (Ravel et al, 1990; Castillo et al, 1999; Crespo et al, 2000; Pressler et al, 2007; D'souza and Vijayaraghavan, 2012; Ma and Luo, 2012; D'souza et al, 2013; Rothermel et al, 2014; Liu et al, 2015; Smith et al, 2015; Bendahmane et al, 2016). From these data, the net functional effect of ACh inputs to the OB can be constructed as enhancing mitral cell selectivity to odorants through increased inhibition and filtering of low amplitude inputs in concert with increased excitability in response to selective odorants; this idea is supported by behavioral and electrophysiological data (Elaagouby et al, 1991; Linster et al, 2001; Wilson et al, 2004; Mandairon et al, 2006; Devore et al, 2014).…”