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

In the mouse olfactory bulb glomerulus, the GABAergic periglomerular (PG) cells provide a major inhibitory drive within the microcircuit. Here we examine GABAergic synapses between these interneurons. At these synapses, GABA is depolarizing and exerts a bimodal control on excitability. In quiescent cells, activation of GABA_A receptors can induce the cells to fire, thereby providing a means for amplification of GABA release in the glomerular microcircuit via GABA-induced GABA release. In contrast, GABA is inhibitory in neurons that are induced to fire tonically. PG–PG interactions are modulated by nicotinic acetylcholine receptors (nAChRs), and our data suggest that changes in intracellular calcium concentrations triggered by nAChR activation can be amplified by GABA release. Our results suggest that bidirectional control of inhibition in PG neurons can allow for modulatory inputs, like the cholinergic inputs from the basal forebrain, to determine threshold set points for filtering out weak olfactory inputs in the glomerular layer of the olfactory bulb via the activation of nAChRs.The balance of excitation and inhibition is critical for the normal functioning of brain networks. Timed inhibition of principal neurons modulates circuit output and contributes to network synchrony and oscillation. GABAergic interneurons play a key role in regulating these network properties (1, 2). Recent findings (e.g., ref. 3), however, have compelled us to move away from a simple view of transmission in the brain, in which glutamate and GABA represent the major excitatory and inhibitory transmitter systems, to a more nuanced interpretation of their roles.GABAergic neurotransmission has both inhibitory and excitatory effects in the CNS. Whereas the inhibitory actions of GABA on principal neurons in different brain regions have been examined extensively, studies of excitatory GABA have focused mostly on the developmental aspects of neuronal growth and synapse formation (4, 5). Recent evidence suggests that GABA can be excitatory in mature neurons as well (with the term “mature” here referring to neurons that are integral parts of established brain networks) (3, 6).Dynamic GABAergic signaling between inhibitory interneurons is less well understood. The common assumption is that GABAergic signaling between these interneurons would lead to disinhibition of principal neurons in a circuit. Excitatory GABA signaling between these interneurons, on the other hand, could serve as a means for amplification of principal cell inhibition. A combination of the two could effectively buffer interneuron firing rates and possibly normalize circuit output in a given area (7).The modularity in brain circuits allows for application of principles gleaned from the study of one defined circuit to other circuits as well. In the olfactory bulb (OB) glomerulus, the GABAergic periglomerular (PG) cells provide a large fraction of the inhibitory drive for information transfer between the olfactory nerve (ON) and mitral cells (MCs), the principal neurons. In this system, the existence of PG–PG synapses has been demonstrated (8), and GABA has been suggested to be depolarizing, yet inhibitory, on these neurons (9). Whether these synapses participate in glomerular signaling either during odor input or during neuromodulation of glomerular output is not yet known.In this paper, we report that GABAergic connections between PG cells have a bimodal effect on excitation depending on the previous activity state of the neurons. Excitation of PG cells by GABA can lead to amplification of glomerular inhibition via GABA-induced GABA release (GIGR). GABA release from PG cells modulates glomerular output on the activation of nicotinic acetylcholine receptors (nAChRs), wherein weak signals from the ON are filtered out while stronger ones are transmitted (10). Our results suggest that bimodal signaling by GABA could be important in determining set points for inhibition thresholds in the glomerular microcircuit.