Activity-dependent formation of the topographic map and the critical period in the development of mammalian olfactory system

Abstract

Neural activity influences every aspect of nervous system development. In olfactory systems, sensory neurons expressing the same odorant receptor project their axons to stereotypically positioned glomeruli, forming a spatial map of odorant receptors in the olfactory bulb. As individual odors activate unique combinations of glomeruli, this map forms the basis for encoding olfactory information. The establishment of this stereotypical olfactory map requires coordinated regulation of axon guidance molecules instructed by spontaneous activity. Recent studies show that sensory experiences also modify innervation patterns in the olfactory bulb, especially during a critical period of the olfactory system development. This review examines evidence in the field to suggest potential mechanisms by which various aspects of neural activity regulate axon targeting. We also discuss the precise functions served by neural plasticity during the critical period.

Keywords: axon guidance; critical period; odor recognition; olfactory map; olfactory receptors (ORs); olfactory sensory neurons (OSNs); spontaneous activity.

Figure 1:

OSN axon pathfinding is governed by spontaneous activity and intracellular signaling. (A)Odor-independent receptor activity determines cAMP levels through activation of G_s to regulate the expression of axon guidance molecules for A-P axis glomerular positioning. Genes involved in determining the D-V and A-P axes are illustrated. Sema3F and Robo2 show high expression levels in the dorsal OSNs, whereas Nrp2 and Slit1 are mainly expressed in the ventral region. Nrp1 and PlxnA1 gradients contribute to the positioning of glomeruli along the A-P. Their expressions are determined by cAMP levels. (B)Spontaneous electrical activity in the OSN is coupled to the OR, likely through G_olf-dependent, instead of G_s-dependent signaling, which results in CNG channel activation. The patterns of activity regulate the expression of guidance molecules involved in axon convergence. High activity levels promote the expression of Kirrel2 and EphA while reducing the levels of Kirrel3, EphrinA, and BIG2. Conversely, low activity inhibits Kirrel2 and EphA expression while increasing Kirrel3, EphrinA, and BIG2 expression. These combination patterns of axon guidance molecules generate homophilic attraction and heterotypic repulsion among the axons to induce convergence. (C)Odor-evoked activity regulates OSN axon convergence depending on the timing and duration of the stimulation. The stimulation windows (middle panel) and corresponding changes (right panel) are color matched.

Figure 2:

A timeline of OSN development and the role of the critical period. (A)The development of olfactory sensory neurons (OSNs) in mice spans from the emergence of pioneer cells around E14.5 to the presence of navigator cells between E18.5 and P10, eventually culminating in the establishment of a fully formed olfactory map (adult). (B)Perturbation during the critical period can alter the projection patterns. Removal of the perturbation before the closure of the critical period allows axons to revert to single glomerular projection. Perturbation lasting beyond the critical period permanently alters OSN axon targeting. (C)Diagram illustrating temporal changes associated with different cell types and Fzd1expression in the OE during perinatal stages.