A specific olfactory bulb interneuron subtype Tpbg/5T4 generated at embryonic and neonatal stages

Abstract

Various mammals have shown that sensory stimulation plays a crucial role in regulating the development of diverse structures, such as the olfactory bulb (OB), cerebral cortex, hippocampus, and retina. In the OB, the dendritic development of excitatory projection neurons like mitral/tufted cells is influenced by olfactory experiences. Odor stimulation is also essential for the dendritic development of inhibitory OB interneurons, such as granule and periglomerular cells, which are continuously produced in the ventricular-subventricular zone throughout life. Based on the morphological and molecular features, OB interneurons are classified into several subtypes. The role for each interneuron subtype in the control of olfactory behavior remains poorly understood due to lack of each specific marker. Among the several OB interneuron subtypes, a specific granule cell subtype, which expresses the oncofetal trophoblast glycoprotein (Tpbg or 5T4) gene, has been reported to be required for odor detection and discrimination behavior. This review will primarily focus on elucidating the contribution of different granule cell subtypes, including the Tpbg/5T4 subtype, to olfactory processing and behavior during the embryonic and adult stages.

Keywords: Tpbg/5T4; activity-dependent development; fate map; granule cells; olfactory bulb.

Figure 1

Cell fate of multiple subtypes of olfactory bulb (OB) interneurons. (A) The mammalian OB is structured into distinct layers: the glomerular layer (GL), external plexiform layer (EPL), mitral cell layer (MCL), and granule cell layer (GCL). Olfactory sensory signals from olfactory sensory neurons (OSN) in the olfactory epithelium (OE) are transmitted by excitatory projection neurons such as mitral cells (MCs) and tufted cells (TCs) to inhibitory interneurons like granule cells (GCs) and periglomerular cells (PGCs). (B) Distribution of neural stem cells in the ventricular-subventricular zone (V/SVZ) in specific areas. Adult OB interneurons are generated in different subregions of the V/SVZ (upper row; a), migrate through the rostral migratory stream (RMS), and subsequently differentiate into distinct subtypes of mature interneurons in the OB, including GCs (G_II, G_III, G_IIIM, and CalR) and PGCs (TH and CalR). (C) Transcriptome cell type classification of whole mouse brain. A transcriptome classification tree is organized into 7 neighborhoods, 34 classes, and 338 subclasses. The subpallium-GABA neighborhood comprises 7 classes, one of which is the OB-IMN-GABA class containing 30 subclasses. Notably, the Frmd7 Gaba_1 subclass includes Tpbg/5T4 and Lgr6 genes. The content in panel (C) is adapted from the extended data figure in the study by Yao et al. (2023), with permission from the journal. (D) Spatial expression of the OBINH-3-[Gad1_Tpbg_Tiam2] subcluster genes in the mouse OB, based on the “Spatial-Portal” website (https://www.spatial-atlas.net/Brain/spatial.html). This site presents a spatial molecular atlas of the adult mouse central nervous system generated by Xiao Wang’s lab with STARmap PLUS, an imaging-based targeted in situ sequencing platform (Shi et al., 2023).

Figure 2

Role of the Tpbg/5T4 GC subtype within the OB neural circuit. (A) Schematic representation of the OB neural circuit. Superficial GCs nearby the MC layer (G_IIIM) harboring Tpbg/5T4 GCs exhibits a preference for establishing connections with the lateral dendrites of external TCs (eTCs) located in the surface segment of the external plexiform layer (EPL). Conversely, GCs situated in the deep GC layer (G_II) predominantly form connections with MCs in the deep segment of the EPL. These distinct pathways of MCs and TCs facilitate the transmission of varied odor information to discrete regions of the olfactory cortex. GL, glomerular layer; EPL, external plexiform layer; MCL, mitral cell layer; GCL, granule cell layer. (B) Two categories of eTCs. Tpbg/5T4 GCs establish dendritic synapses with two types of eTCs: burst type eTCs lacking lateral dendrites that exhibit frequent spontaneous firing; non-burst type eTCs possessing lateral dendrites that do not exhibit such firing behavior. (C) Tpbg/5T4 GCs connecting to non-burst type eTCs that display reduced dendritic branching in Tpbg/5T4-knockout (KO) mice. Notably, GABAergic inputs to non-burst type eTCs are significantly diminished in Tpbg/5T4 KO mice, whereas inputs to burst type eTCs remain unaffected. Consequently, olfactory functions such as odor detection and discrimination are impaired in Tpbg/5T4 KO mice. (D) Integration of Tpbg/5T4 GCs produced at embryonic and adult stages. Bromodeoxyuridine labeling reveals that embryonic-born Tpbg/5T4 GCs are predominantly integrated in the OB (depicted in blue), with minimal integration observed in adult-born Tpbg/5T4 GCs (depicted in green) (Takahashi et al., 2016).