Interactions between Guidance Cues and Neuronal Activity: Therapeutic Insights from Mouse Models

Abstract

Topographic mapping of neural circuits is fundamental in shaping the structural and functional organization of brain regions. This developmentally important process is crucial not only for the representation of different sensory inputs but also for their integration. Disruption of topographic organization has been associated with several neurodevelopmental disorders. The aim of this review is to highlight the mechanisms involved in creating and refining such well-defined maps in the brain with a focus on the Eph and ephrin families of axon guidance cues. We first describe the transgenic models where ephrin-A expression has been manipulated to understand the role of these guidance cues in defining topography in various sensory systems. We further describe the behavioral consequences of lacking ephrin-A guidance cues in these animal models. These studies have given us unexpected insight into how neuronal activity is equally important in refining neural circuits in different brain regions. We conclude the review by discussing studies that have used treatments such as repetitive transcranial magnetic stimulation (rTMS) to manipulate activity in the brain to compensate for the lack of guidance cues in ephrin-knockout animal models. We describe how rTMS could have therapeutic relevance in neurodevelopmental disorders with disrupted brain organization.

Keywords: ephrin; neuronal activity; neuroplasticity; rTMS; sensory systems; topography.

Figure 3

(A) Representation of the projections in the auditory system (cochlea) where type I SGNs expressing EphA4 project to OHCs that highly express ephrin-A5 ligands [55]. Note that their gradient is not well defined and therefore is not depicted here. Figure created using data from [55]. (B) Representation of the projections in the vomeronasal system where projections from VNO with EphA6 expression target regions with a similar expression of ephrin-A5 in the AOB [63], therefore unlike other sensory systems, projections in the vomeronasal system are guided by attraction. Figure created using data from [63] (SGN—spiral ganglion neurons; IHC—inner hair cells; OHC—outer hair cells; VNO—vomeronasal organ; AOB—accessory olfactory bulb).

Figure 1

Schematic representation of the visual system circuitry guided by Eph-ephrin gradients in different regions of the adult mouse brain. The endpoints of the projections are represented by a circle (dLGN-dorsolateral geniculate nucleus; SC-superior colliculus; V1-primary visual system).

Figure 2

Schematic representation of the projections from (1) whisker barrels to (2) brainstem, (3) thalamus, and to (4) contralateral barrel cortex in adult mice [47]. Ventrobasal thalamus projects to the barrel cortex, which is guided by their complementary gradient of EphA4 receptor and ephrin-A5 ligands, respectively [49]. The endpoints of the projections are represented by a circle. Figure created using data from [47,49].