Balancing extrasynaptic excitation and synaptic inhibition within olfactory bulb glomeruli

Abstract

Glutamatergic transmission in the brain typically occurs at well-defined synaptic connections, but increasing evidence indicates that neural excitation can also occur through activation of “extrasynaptic” glutamate receptors. Here we investigated the underlying mechanisms and functional properties of extrasynaptic signals that are part of a feedforward path of information flow in the olfactory bulb. This pathway involves glutamatergic interneurons, external tufted cells (eTCs), that are excited by olfactory sensory neurons (OSNs) and in turn excite output mitral cells (MCs) extrasynaptically. Using pair- and triple-cell recordings in rat bulb slices (of either sex), combined with ultrastructural approaches, we first present evidence that eTC-to-MC signaling results from “spillover” of glutamate released at eTC synapses onto GABAergic periglomerular (PG) cells in glomeruli. Thus, feedforward excitation is an indirect result of and must co-occur with activation of inhibitory circuitry. Next, to examine the dynamics of the competing signals, we assayed the relationship between the number of spikes in eTCs and excitation of MCs or PG cells in pair-cell recordings. This showed that extrasynaptic excitation in MCs is very weak due to single spikes but rises sharply and supralinearly with increasing spikes, differing from sublinear behavior for synaptic excitation of PG cells. Similar dynamics leading to a preference for extrasynaptic excitation were also observed during recordings of extrasynaptic and inhibitory currents in response to OSN input of increasing magnitude. The observed alterations in the balance between extrasynaptic excitation and inhibition in glomeruli with stimulus strength could underlie an intraglomerular mechanism for olfactory contrast enhancement.

Significance Statement Glutamatergic transmission in the brain occurs primarily at anatomically defined synaptic connections, but increasing evidence supports the prevalence of “extrasynaptic” mechanisms. Here we investigated extrasynaptic glutamatergic transmission between two types of excitatory cells in glomeruli of the rodent olfactory bulb, as well as its relationship with respect to local GABAergic inhibition. Our results indicate that weak stimuli preferentially favor inhibition over extrasynaptic excitation, but differences in the non-linear properties between extrasynaptic excitation and inhibition result in strong stimuli favoring extrasynaptic excitation. The shift in balance between extrasynaptic excitation and inhibition with stimulus strength could provide a novel intraglomerular mechanism for olfactory contrast enhancement, helping the brain discriminate different but similar odors.