Presynaptic NMDARs cooperate with local spikes toward GABA release from the reciprocal olfactory bulb granule cell spine

Lage-Rupprecht, Vanessa; Zhou, Li; Bianchini, Gaia; Aghvami, S. Sara; Mueller, Max; Rózsa, Balázs; Sassoè‐Pognetto, Marco; Egger, Veronica

doi:10.7554/elife.63737

Cited by 7 publications

(14 citation statements)

References 88 publications

(97 reference statements)

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“…Interestingly, recurrent GABA release was also dependent on NMDAR activation, pointing towards a cooperative mechanism for which we obtained further evidence via ultrastructural demonstration of NMDARs within the GABAergic active zone of the spine (Fig. 1b; Lage -Rupprecht et al 2020). This opens the possibility of cooperative overlapping Ca 2+ domains between NMDARs and HVACCs within the GABAergic active zone and, in particular, may establish a close distance between NMDARs and the release sensor at the readily releasable vesicles.…”

Section: Recent Findings 1: Recurrent Inhibition By the Reciprocal Spsupporting

confidence: 57%

Olfactory bulb granule cells: specialized to link coactive glomerular columns for percept generation and discrimination of odors

Egger

Kuner

2021

Cell Tissue Res

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The role of granule cells in olfactory processing is surrounded by several enigmatic observations, such as the purpose of reciprocal spines and the mechanisms for GABA release, the apparently low firing activity and recurrent inhibitory drive of granule cells, the missing proof for functional reciprocal connectivity, and the apparently negligible contribution to lateral inhibition. Here, we summarize recent results with regard to both the mechanisms of GABA release and the behavioral relevance of granule cell activity during odor discrimination. We outline a novel hypothesis that has the potential to resolve most of these enigmas and allows further predictions on the function of granule cells in odor processing. Briefly, recent findings imply that GABA release from the reciprocal spine requires a local spine action potential and the cooperative action of NMDA receptors and high voltage-activated Ca2+ channels. Thus, lateral inhibition is conditional on activity in the principal neurons connected to a granule cell and tightly intertwined with recurrent inhibition. This notion allows us to infer that lateral inhibition between principal neurons occurs “on demand,” i.e., selectively on coactive mitral and tufted cells, and thus can provide directed, dynamically switched lateral inhibition in a sensory system with 1000 input channels organized in glomerular columns. The mechanistic underpinnings of this hypothesis concur with findings from odor discrimination behavior in mice with synaptic proteins deleted in granule cells. In summary, our hypothesis explains the unusual microcircuit of the granule cell reciprocal spine as a means of olfactory combinatorial coding.

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Section: Recent Findings 1: Recurrent Inhibition By the Reciprocal Spsupporting

confidence: 57%

Olfactory bulb granule cells: specialized to link coactive glomerular columns for percept generation and discrimination of odors

Egger

Kuner

2021

Cell Tissue Res

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“…Olfaction begins in the olfactory epithelium (OE) located in the nasal cavity [5]. Its sensory bipolar neurons (OSN) have a peripheral dendrite which is responsible for odour sensation, and a central axon transmitting the stimuli-via glomerular synapses-to the glutamatergic cells of the olfactory bulb (OB) [5][6][7]. Another important cell type in the OB is the GABAergic granule cell, interacting with the neurotransmission of glutamatergic neurones [7].…”

Section: Introductionmentioning

confidence: 99%

“…Its sensory bipolar neurons (OSN) have a peripheral dendrite which is responsible for odour sensation, and a central axon transmitting the stimuli-via glomerular synapses-to the glutamatergic cells of the olfactory bulb (OB) [5][6][7]. Another important cell type in the OB is the GABAergic granule cell, interacting with the neurotransmission of glutamatergic neurones [7]. The axon bundles of the glutamatergic cells form the olfactory tract and terminate in primary and secondary olfactory areas (i.e., anterior olfactory nucleus (AON), olfactory tubercle (OT), piriform cortex (PC), amygdala (AM) and entorhinal cortex (EC)) [8] (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

The Role of TRPA1 Channels in the Central Processing of Odours Contributing to the Behavioural Responses of Mice

et al. 2021

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Transient receptor potential ankyrin 1 (TRPA1), a nonselective cation channel, contributes to several (patho)physiological processes. Smell loss is an early sign in several neurodegenerative disorders, such as multiple sclerosis, Parkinson’s and Alzheimer’s diseases; therefore, we focused on its role in olfaction and social behaviour with the aim to reveal its potential therapeutic use. The presence of Trpa1 mRNA was studied along the olfactory tract of mice by combined RNAscope in situ hybridisation and immunohistochemistry. The aversive effects of fox and cat odour were examined in parallel with stress hormone levels. In vitro calcium imaging was applied to test if these substances can directly activate TRPA1 receptors. The role of TRPA1 in social behaviour was investigated by comparing Trpa1 wild-type and knockout mice (KO). Trpa1 mRNA was detected in the olfactory bulb and piriform cortex, while its expression was weak in the olfactory epithelium. Fox, but not cat odour directly activated TRPA1 channels in TRPA1-overexpressing Chinese Hamster Ovary cell lines. Accordingly, KO animals showed less aversion against fox, but not cat odour. The social interest of KO mice was reduced during social habituation–dishabituation and social interaction, but not during resident–intruder tests. TRPA1 may contribute to odour processing at several points of the olfactory tract and may play an important role in shaping the social behaviour of mice. Thus, TRPA1 may influence the development of certain social disorders, serving as a potential drug target in the future.

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“…Here, we focused on the role of GCs (1) because GCs are the most abundant neuronal type of the olfactory bulb (in rat > 2•10 6 , Richard et al, 2010, versus EPL interneurons <1•10 5 , e.g., Parrish-Aungst et al, 2007 and also provide the majority of inhibitory inputs onto MCs and TCs compared to parvalbumin interneurons (approximately 90%, Matsuno et al, 2017), (2) because their contribution to inhibition is not well understood (e.g., Fukunaga et al, 2014;Burton, 2017), and (3) because of our long-standing interest in the function of the reciprocal GC spine that has by now allowed us to characterize the operation of the spine microcircuit with regard to its output to MCs. For example, recurrent inhibition by GCs can already be exerted at the single-spine level, since a local glutamatergic MC input can activate the reciprocal microcircuit (Lage-Rupprecht et al, 2020), whereas it is as of yet unknown whether EPL interneuron dendrites can release GABA in response to a single MC AP without further excitation from other inputs.…”

Section: Introductionmentioning

confidence: 99%

“…Conversely, MC lateral dendrites have been studied both experimentally and in simulations (e.g., Lowe, 2002;Xiong and Chen, 2002;Debarbieux et al, 2003;McTavish et al, 2012;Li and Cleland, 2013;McIntyre and Cleland, 2016). Here, we supplemented these studies with functional data on unitary GC input to MC lateral dendrites (from Lage-Rupprecht et al, 2020) and anatomical data on synaptic density (see Section "Anatomical Basis of Mitral Cell-Granule Cell Dendrodendritic Connectivity") in order to estimate GC-mediated recurrent inhibition.…”

Section: Introductionmentioning

confidence: 99%

Anatomical and Functional Connectivity at the Dendrodendritic Reciprocal Mitral Cell–Granule Cell Synapse: Impact on Recurrent and Lateral Inhibition

Aghvami

Kubota²,

Egger³

2022

Front. Neural Circuits

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In the vertebrate olfactory bulb, reciprocal dendrodendritic interactions between its principal neurons, the mitral and tufted cells, and inhibitory interneurons in the external plexiform layer mediate both recurrent and lateral inhibition, with the most numerous of these interneurons being granule cells. Here, we used recently established anatomical parameters and functional data on unitary synaptic transmission to simulate the strength of recurrent inhibition of mitral cells specifically from the reciprocal spines of rat olfactory bulb granule cells in a quantitative manner. Our functional data allowed us to derive a unitary synaptic conductance on the order of 0.2 nS. The simulations predicted that somatic voltage deflections by even proximal individual granule cell inputs are below the detection threshold and that attenuation with distance is roughly linear, with a passive length constant of 650 μm. However, since recurrent inhibition in the wake of a mitral cell action potential will originate from hundreds of reciprocal spines, the summated recurrent IPSP will be much larger, even though there will be substantial mutual shunting across the many inputs. Next, we updated and refined a preexisting model of connectivity within the entire rat olfactory bulb, first between pairs of mitral and granule cells, to estimate the likelihood and impact of recurrent inhibition depending on the distance between cells. Moreover, to characterize the substrate of lateral inhibition, we estimated the connectivity via granule cells between any two mitral cells or all the mitral cells that belong to a functional glomerular ensemble (i.e., which receive their input from the same glomerulus), again as a function of the distance between mitral cells and/or entire glomerular mitral cell ensembles. Our results predict the extent of the three regimes of anatomical connectivity between glomerular ensembles: high connectivity within a glomerular ensemble and across the first four rings of adjacent glomeruli, substantial connectivity to up to eleven glomeruli away, and negligible connectivity beyond. Finally, in a first attempt to estimate the functional strength of granule-cell mediated lateral inhibition, we combined this anatomical estimate with our above simulation results on attenuation with distance, resulting in slightly narrowed regimes of a functional impact compared to the anatomical connectivity.

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Presynaptic NMDARs cooperate with local spikes toward GABA release from the reciprocal olfactory bulb granule cell spine

Cited by 7 publications

References 88 publications

Olfactory bulb granule cells: specialized to link coactive glomerular columns for percept generation and discrimination of odors

Olfactory bulb granule cells: specialized to link coactive glomerular columns for percept generation and discrimination of odors

The Role of TRPA1 Channels in the Central Processing of Odours Contributing to the Behavioural Responses of Mice

Anatomical and Functional Connectivity at the Dendrodendritic Reciprocal Mitral Cell–Granule Cell Synapse: Impact on Recurrent and Lateral Inhibition

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