Spontaneous Afferent Activity Carves Olfactory Circuits

Abstract

Electrical activity has a key role in shaping neuronal circuits during development. In most sensory modalities, early in development, internally generated spontaneous activity sculpts the initial layout of neuronal wiring. With the maturation of the sense organs, the system relies more on sensory-evoked electrical activity. Stimuli-driven neuronal discharge is required for the transformation of immature circuits in the specific patterns of neuronal connectivity that subserve normal brain function. The olfactory system (OS) differs from this organizational plan. Despite the important role of odorant receptors (ORs) in shaping olfactory topography, odor-evoked activity does not have a prominent role in refining neuronal wiring. On the contrary, afferent spontaneous discharge is required to achieve and maintain the specific diagram of connectivity that defines the topography of the olfactory bulb (OB). Here, we provide an overview of the development of olfactory topography, with a focus on the role of afferent spontaneous discharge in the formation and maintenance of the specific synaptic contacts that result in the topographic organization of the OB.

Keywords: activity; development; olfaction; plasticity; spontaneous; topography.

Figure 1

Schematic of the connectivity between the olfactory epithelium (OE) and the olfactory bulb (OB). (A,B) In controls, (A) olfactory sensory neurons (OSNs) expressing the same odorant receptor (OR; i.e., same color) project their axons in specific loci of the OB to form the corresponding glomeruli (circle with a single color). In Kir2.1 mice (B) OSNs expressing the same OR (same colors) project their axons not only to the main homogeneous glomerulus (circle with a single color) but also to multiple additional heterogeneous glomeruli (indicated by a circle with two colors). (C) Schematic of odor columns. OSNs expressing the same OR form synapses with the postsynaptic cells, namely the mitral and tufted (M/T) cells, along with the periglomerular cells at the glomerular level. Within the external plexiform layer, M/T cells form synapses with the granule cells. Each glomerulus defines, therefore, a functional unit, indicated as an odor column that processes the sensory information related to a given OR. GL, glomerulus; GC, granule cells.

Figure 2

The connection between isofunctional glomeruli. (A) Schematic of the intrabulbar link between homologous glomeruli. External tufted cells (ETC) connected to a given glomerulus form excitatory synapses (+) onto the dendrites of the granule cells (GC) in a restricted region of the internal plexiform layer on the opposite side of the olfactory bulb (OB). The GC in turn forms inhibitory synapses (−) on the ETC connected to the homologous glomerulus. This connection is reciprocal. (B,C) In control mice, during the early stage of development, ETC related to a given glomerulus, project their axons to a broad area on the opposite side of the OB, beneath, but not limited, to the homologous glomerulus. (B) Then, the ETC projection undergoes a refinement process, such that its extension becomes limited to the homologous glomerulus (C). (D,E) In mice with reduced afferent spontaneous activity (Kir2.1 mice), ETC’s large projection first formed beneath the homologous glomerulus (D) on the opposite side of the bulb, remains larger, assuming the features of unrefined connectivity (E). OSN, olfactory sensory neurons; GL, glomerular layer; EPL, external plexiform layer; MCL, mitral cell layer; IPL, internal plexiform layer; GCL, granule cell layer.

Figure 3

Plasticity in the OB. (A) Schematic illustrating the inducible nature of the Kir2.1 construct. Mice carrying OMP-IRES-tTA and tetO-Kir2.1-IRES-tau-lacZ alleles express Kir2.1 and tauLacZ only in the absence of doxycycline. Doxycycline suppresses the expression of Kir 2.1. (B,E) Schematic of the experimental strategy: doxycycline is supplied during pregnancy until postnatal day 30 (P30). The organization of connection was analyzed at P30 and P60. (C) The specificity of connectivity is present in Kir.2.1 mice at P30, upon suppression of Kir2.1 expression (D). The overexpression of Kir2.1 between P30 and P60 induces regression of the already refined connectivity (D). (F) Similarly, homologous glomeruli are linked in a point-to-point manner at P30, upon doxycycline treatment. (G) However, the overexpression of Kir2.1 between P30 and P60 leads to unrefined connectivity between the homologous glomeruli.