Deficits in olfactory system neurogenesis in neurodevelopmental disorders

Abstract

The role of neurogenesis in neurodevelopmental disorders (NDDs) merits much attention. The complex process by which stem cells produce daughter cells that in turn differentiate into neurons, migrate various distances, and form synaptic connections that are then refined by neuronal activity or experience is integral to the development of the nervous system. Given the continued postnatal neurogenesis that occurs in the mammalian olfactory system, it provides an ideal model for understanding how disruptions in distinct stages of neurogenesis contribute to the pathophysiology of various NDDs. This review summarizes and discusses what is currently known about the disruption of neurogenesis within the olfactory system as it pertains to attention-deficit/hyperactivity disorder, autism spectrum disorder, Down syndrome, Fragile X syndrome, and Rett syndrome. Studies included in this review used either human subjects, mouse models, or Drosophila models, and lay a compelling foundation for continued investigation of NDDs by utilizing the olfactory system.

Keywords: neurodevelopmental disorders; neurogenesis; olfactory system.

Figure 1.. Lifelong neurogenesis in the mouse olfactory system.

A. Schematic of the olfactory epithelium showing major cell types. Note the pseudostratified organization of the OE, with basally located stem cells and apically located sustentacular cells and mature OSNs. B. Generation of olfactory sensory neurons (OSNs) and sustentacular cells from globose basal cells (GBCs) and horizontal basal cells (HBCs). C. Ongoing neurogenesis of granule cells and periglomerular cells from neural stem cells in the subventricular zone (SVZ) lining the lateral ventricle. Neuroblasts migrate via the rostral migratory stream (RMS) to the OB. Neurons reach their final location via radial migration to the granule cell layer (granule cells) or the glomerular layer (periglomerular cells). D. Differentiation of SVZ neural stem cells to generate granule cells and periglomerular cells. Created with BioRender.com. Panel A was adapted from “Mouse Olfactory Epithelium”, by BioRender.com (2023). Retrieved from https://app.biorender.com/biorender-templates

Figure 2.. Schematic of key axon guidance molecules relevant to OSNs.

Various signaling mechanisms contribute to OSN axon guidance and synapse formation, including ephrin-Eph signaling, Slit-Robo signaling and Sema-neuropilin-plexin signaling. Ephrin-Eph signaling involves ephrin ligands binding to Eph family receptor tyrosine kinases and mediates short distance cell-cell signaling. Repulsive interactions occur between EphrinA-expressing OSN axons and EphA-expressing mitral and tufted cells, and between EphrinA5 and EphA5, which are expressed on non-overlapping subsets of OSN axons. Slit is a secreted ligand that primarily binds to the Robo receptor. Repulsion occurs between Robo-2-expressing OSN axons and Slit1- and Slit-3 secreted by mitral cells, as well as between subsets of OSNs expressing Robo-2, Slit-1 and Slit2, and Robo-1-expressing olfactory ensheathing cells. Sema-neuropilin-plexin signaling consists of secreted semaphorin ligands complexing with neuropilin co-receptors and plexin receptors, and serves several functions relevant to OSNs: Sema 3F secreted by mitral, tufted and periglomerular cells in the OB is important for pruning of neuropilin-2-expressing OSN axons that overshoot into the EPL (top left); repulsion occurs between non-overlapping populations of OSN axons expressing Sema 3F and neuropilin-2 (top right); Sema 3A secreted by mitral and tufted cells repels neuropilin-1-expressing OSN axons (bottom left); and repulsion between Sema 7A secreted by OSN axons and plexin C1 expressed by mitral and tufted cells is required for OSN synapse formation (bottom right) (Inoue et al., 2018). See Cho et al., 2009; Dorrego-Rivas & Grubb, 2022 and Francia & Lodovichi, 2021 for further details. Created with BioRender.com.

Figure 3.. Factors that positively and negatively influence activity- and experience-dependent refinement of neural circuits.

Negative: the absence of olfactory sensory input can disrupt glomerular refinement in the OB. Negative early life experiences, such as maternal separation and reduced bedding/nesting in the case of rodents; or malnourishment, an unstable household environment, and psychological stress in the case of children, can also lead to disrupted neuronal circuitry. Positive: olfactory sensory input from various odor molecules influences glomerular refinement. Positive early life experiences, such as maternal handling and an enriched environment in the case of rodents; or positive attention, a secure household, and enrichment in the case of children, can positively influence the refinement of neuronal circuitry. Created with BioRender.com.