The role of calretinin-expressing granule cells in olfactory bulb functions and odor behavior

Abstract

The adult mouse olfactory bulb is continuously supplied with new neurons that mostly differentiate into granule cells (GCs). Different subtypes of adult-born GCs have been identified, but their maturational profiles and their roles in bulbar network functioning and odor behavior remain elusive. It is also not known whether the same subpopulations of GCs born during early postnatal life (early-born) or during adulthood (adult-born) differ in their morpho-functional properties. Here, we show that adult-born calretinin-expressing (CR+) and non-expressing (CR−) GCs, as well as early-born CR+ GCs, display distinct inhibitory inputs but indistinguishable excitatory inputs and similar morphological characteristics. The frequencies of inhibitory post-synaptic currents were lower in early-born and adult-born CR+ GCs than in adult-born CR− neurons. These findings were corroborated by the reduced density of gephyrin+ puncta on CR+ GCs. CR+ GCs displayed a higher level of activation following olfactory tasks based on odor discrimination, as determined by an immediate early gene expression analysis. Pharmacogenetic inhibition of CR+ GCs diminished the ability of the mice to discriminate complex odor mixtures. Altogether, our results indicate that distinct inhibitory inputs are received by adult-born CR+ and CR− GCs, that early- and adult-born CR+ neurons have similar morpho-functional properties, and that CR+ GCs are involved in complex odor discrimination tasks.

Dynamic Changes in the Neurogenic Potential in the Ventricular–Subventricular Zone of Common Marmoset during Postnatal Brain Development

“…5). Calretinin+ granule cells are involved in complex odor discrimination tasks in rodents (Hardy D et al 2018), and their production reaches a peak in the early neonatal period in mice (Batista-Brito R et al 2008).…”

CPEB4-Dependent Neonate-Born Granule Cells Are Required for Olfactory Discrimination

“…The bulbar wiring circuit is composed of heterogeneous GC subtypes, which are identified according to their morphological, electrophysiological and/or molecular differences as well as topological distribution in the GCL (Takahashi et al, 2018). Deletion or inhibition of single subtype GCs (i.e., trophoblastic glycoprotein 5T4-positive or calretinin-positive GCs) causes significant olfactory dysfunctions (Takahashi et al, 2016; Hardy et al, 2018), suggesting their functions in the olfactory circuit cannot be substituted by other GC subtypes. Further investigations are needed to understand the spatial and temporal interaction among heterogeneous populations of OB interneurons for processing odor discrimination.…”

“…Thus, SVZ-derived GCs, which accumulate approximately after postnatal 2–3 weeks and reach a plateau of ~40% of total GC population in the OB at 3 months (Cushman et al, 2012), continue turnover to maintain and renew the inhibitory circuits throughout life (Imayoshi et al, 2008; Mouret et al, 2009; Lazarini et al, 2014). The two waves of spatiotemporally distinct neurogenesis produce bulbar GCs of high heterogeneity (Kelsch et al, 2007; Batista-Brito et al, 2008; Hardy et al, 2018). Moreover, neonate-born GCs, almost all surviving to adulthood as compared with only ~50% survival of adult-born GCs, are distributed in the superficial part of the GCL closer to MCs (Lemasson et al, 2005), so the local and SVZ neurogenesis likely produce GCs to establish spatiotemporally distinct circuits.…”

Developmental Potential and Plasticity of Olfactory Epithelium Stem Cells Revealed by Heterotopic Grafting in the Adult Brain

“…To determine whether cells in the OB after a grafting of OE-derived NSCs express molecular markers of mature neurons, we performed immunolabeling for neuronal markers NeuN and calretinin, which is expressed by a subpopulation of endogenous adult-born neurons (Hardy et al, 2018). The vast majority of grafted cells express the markers of mature neurons, and no differences in the expression of NeuN (endogenous: 93.4% ± 2.1%; grafted: 93.5% ± 1.2%; Figure 3B) and calretinin (endogenous: 13.3% ± 2.7%; grafted: 14.7% ± 2.4%, n = 525 and 121 cells, respectively, from 2 to 3 mice) between the grafted and endogenous neurons were observed.…”

“…Adultborn OB interneurons are axonless cells and form dendro-dendritic reciprocal synapses with principal neurons (Lledo and Saghatelyan, 2005;Whitman and Greer, 2007). They are involved in odor processing, and altering their number and/or function affects several types of olfactory behavior, including fine odor discrimination, short-term odor memory, and olfactory learning (Alonso et al, 2012;Breton-Provencher et al, 2009;Grelat et al, 2018;Hardy et al, 2018;Malvaut et al, 2017). Thus, NSCs in the OE and SVZ are exposed to completely different micro-environmental cues, undergo different developmental trajectories, and generate completely different neuronal subtypes with distinct morpho-functional characteristics.…”