Cholecystokinin: An Excitatory Modulator of Mitral/Tufted Cells in the Mouse Olfactory Bulb

Abstract

Cholecystokinin (CCK) is widely distributed in the brain as a sulfated octapeptide (CCK-8S). In the olfactory bulb, CCK-8S is concentrated in two laminae: an infraglomerular band in the external plexiform layer, and an inframitral band in the internal plexiform layer (IPL), corresponding to somata and terminals of superficial tufted cells with intrabulbar projections linking duplicate glomerular maps of olfactory receptors. The physiological role of CCK in this circuit is unknown. We made patch clamp recordings of CCK effects on mitral cell spike activity in mouse olfactory bulb slices, and applied immunohistochemistry to localize CCKB receptors. In cell-attached recordings, mitral cells responded to 300 nM –1 µM CCK-8S by spike excitation, suppression, or mixed excitation-suppression. Antagonists of GABAA and ionotropic glutamate receptors blocked suppression, but excitation persisted. Whole-cell recordings revealed that excitation was mediated by a slow inward current, and suppression by spike inactivation or inhibitory synaptic input. Similar responses were elicited by the CCKB receptor-selective agonist CCK-4 (1 µM). Excitation was less frequent but still occurred when CCKB receptors were blocked by LY225910, or disrupted in CCKB knockout mice, and was also observed in CCKA knockouts. CCKB receptor immunoreactivity was detected on mitral and superficial tufted cells, colocalized with Tbx21, and was absent from granule cells and the IPL. Our data indicate that CCK excites mitral cells postsynaptically, via both CCKA and CCKB receptors. We hypothesize that extrasynaptic CCK released from tufted cell terminals in the IPL may diffuse to and directly excite mitral cell bodies, creating a positive feedback loop that can amplify output from pairs of glomeruli receiving sensory inputs encoded by the same olfactory receptor. Dynamic plasticity of intrabulbar projections suggests that this could be an experience-dependent amplification mechanism for tuning and optimizing olfactory bulb signal processing in different odor environments.

Thresholding of sensory inputs by extrasynaptic glutamate receptors in olfactory bulb glomeruli

“…For example, negative coupling between neural activity during spike bursts and glutamate uptake by astroglial transporters has been reported (Armbruster et al, 2016). Another scenario that we cannot completely exclude is one in which repetitive spiking in eTCs recruits the release of excitatory neurotransmitters other than glutamate (Ma et al, 2013). In our experiments, we found that blockade of ionotropic glutamate receptors reduced most (∼70%) of even the largest EC extra responses ( Fig.…”

Cholecystokinin selectively activates short axon cells to enhance inhibition of olfactory bulb output neurons

“…However, this prediction contradicted a recent report that CCK at 1 μ m excited majority of MTCs (Ma et al . ). Considering that cesium and QX‐314 in the voltage clamp pipette solution non‐selectively block K + , Na + and other ion channels (Perkins & Wong, ; Talbot & Sayer, ), we then examined the effects of CCK on the intrinsic electrophysiological properties of a separate sets of MTCs with intact apical dendrites in current clamp with K + ‐based intracellular solution containing no QX‐314 in the presence of NBQX, APV and GBZ to eliminate circuit influence.…”

“…Indeed, a recent study showed that CCK mainly excited MTCs (Ma et al . ). However, at least two pieces of evidence support the idea that the CCK‐enhanced synaptic inhibition of MTCs is not a result of feedback inhibitory input following direct excitation of MTCs.…”

“…A recent study showed that CCK produced excitatory or excitatory followed by inhibitory actions on mitral cells (Ma et al . ), which are the principal OB output neurons. However, the CCK concentration used in that study was relatively high (1 μ m ) given that neuropeptides are normally released from neurons at extremely low concentrations in the nanomolar range (Ghijsen et al .…”

Possible role of calcitonin gene‐related peptide in trigeminal modulation of glomerular microcircuits of the rodent olfactory bulb

“…This bottom-up processing of afferent signals is controlled by modulatory top-down signals, which reach the olfactory bulb from various cortical areas and other brain regions through centrifugal innervation (Matsutani & Yamamoto, 2008;Mouret et al, 2009;Boyd et al, 2012;Nunez-Parra et al, 2013). Cholinergic, serotonergic and adrenergic neuromodulation of bulb circuits have recently been examined in detail (Li & Cleland, 2013;Devore et al, 2014;Eckmeier & Shea, 2014;Rothermel et al, 2014;Schmidt & Strowbridge, 2014;Liu et al, 2015;Parsa et al, 2015;Smith et al, 2015;Brill et al, 2016;Kapoor et al, 2016), and other systems contribute as well (Tobin et al, 2010;Ma et al, 2013).…”