Disinhibition of olfactory bulb granule cells accelerates odour discrimination in mice

Abstract

Granule cells are the dominant cell type of the olfactory bulb inhibiting mitral and tufted cells via dendrodendritic synapses; yet the factors regulating the strength of their inhibitory output, and, therefore, their impact on odour discrimination, remain unknown. Here we show that GABAAR β3-subunits are distributed in a somatodendritic pattern, mostly sparing the large granule cell spines also known as gemmules. Granule cell-selective deletion of β3-subunits nearly abolishes spontaneous and muscimol-induced currents mediated by GABAA receptors in granule cells, yet recurrent inhibition of mitral cells is strongly enhanced. Mice with disinhibited granule cells require less time to discriminate both dissimilar as well as highly similar odourants, while discrimination learning remains unaffected. Hence, granule cells are controlled by an inhibitory drive that in turn tunes mitral cell inhibition. As a consequence, the olfactory bulb inhibitory network adjusts the speed of early sensory processing.

An increase in neural stem cells and olfactory bulb adult neurogenesis improves discrimination of highly similar odorants

“…Second, many studies investigated the role of adult SVZ neurogenesis by depleting NSC and/or altering the properties of the neurons themselves at the level of their migration, survival, integration, and/or electrophysiological activity (Mouret et al, 2009;Abraham et al, 2010;Alonso et al, 2012;Gschwend et al, 2015;Nunes & Kuner, 2015;Wang et al, 2015). Second, many studies investigated the role of adult SVZ neurogenesis by depleting NSC and/or altering the properties of the neurons themselves at the level of their migration, survival, integration, and/or electrophysiological activity (Mouret et al, 2009;Abraham et al, 2010;Alonso et al, 2012;Gschwend et al, 2015;Nunes & Kuner, 2015;Wang et al, 2015).…”

“…To mark such age-matched cohort of newborn neurons in 4D À and 4D + mice, we then crossed the homozygous 4D À and 4D + lines with RCE GFP-flox+/+ mice (Miyoshi et al, 2010), thus, labeling nestin-CreERt2+ NSC upon Tam administration by GFP, irrespective from the presence or absence of RFP. 4D-derived granule neurons expressed the presynaptic vesicular GABA transporter VIAAT that colocalized with the post-synaptic marker gephyrin (Nunes & Kuner, 2015; Fig 3C). Morphometric and 3D-Sholl analyses revealed that spine density (0.36 AE 0.02 vs. 0.33 AE 0.03 spines/lm, 4D À and 4D + , respectively, P = 0.44), total dendritic length (0.78 AE 0.6 and 0.66 AE 0.8 mm, P = 0.26), and arborization (intersections as a function of distance from the soma F (1,28) = 0.61, P = 0.44) were comparable in granule cells derived from 4D À and 4D + NSC ( Fig 3B) and fitting well with previous reports (Abraham et al, 2010;Scotto-Lomassese et al, 2011;Breton-Provencher et al, 2016).…”

“…Similarly, impairing the migration or survival of newborn neurons had either no effect (Kim et al, 2007) or inhibited odor discrimination (Gheusi et al, 2000;Bath et al, 2008). Moreover, activating newly integrated cells was reported to facilitate learning and memory by some studies (Alonso et al, 2012;Gschwend et al, 2015), while, conversely, others showed that enhancing the inhibitory activity of all granule cells in the OB improved odor discrimination time but not learning or memory (Abraham et al, 2010;Nunes & Kuner, 2015). Moreover, activating newly integrated cells was reported to facilitate learning and memory by some studies (Alonso et al, 2012;Gschwend et al, 2015), while, conversely, others showed that enhancing the inhibitory activity of all granule cells in the OB improved odor discrimination time but not learning or memory (Abraham et al, 2010;Nunes & Kuner, 2015).…”

CaMKIIα Expression Defines Two Functionally Distinct Populations of Granule Cells Involved in Different Types of Odor Behavior

“…Despite the fact that GCs make up the largest neuronal population in the OB with neurochemically distinct subtypes, little is known about their functional heterogeneity. Studies aimed at addressing their roles in sensory information processing and odor behavior have usually considered them as a homogeneous population of interneurons [4,5,18]. Using in vivo two-photon imaging of GCaMP6s-infected GCs, we identified two types of GCs based on their level of spontaneous activity and their responses to odor stimulation.…”

“…They establish reciprocal dendro-dendritic synapses with the lateral dendrites of principal neurons and play a major role in odor information processing by synchronizing principal cell activity via lateral and recurrent inhibitions [2,3]. The synchronization of principal neurons by GCs plays an important role in neuronal pattern separation by improving odor discrimination and disambiguating overlapping sensory maps evoked by similar odorants [4,5]. In vivo twophoton Ca 2+ imaging revealed, however, that odor responses by GCs are temporally and spatially heterogeneous [6].…”