Repurposing developmental mechanisms in the adult nervous system

Abstract

Molecules and cellular processes important for nervous system development can be repurposed in adulthood for the regulation of adult neurogenesis, synaptic plasticity, and neural regeneration following injury or degeneration. Efforts to recapitulate neural development in order to ameliorate injury or disease are promising, but these often fall short of functional restoration due in part to our incomplete understanding of how these damaged circuits initially developed. Despite these limitations, such strategies provide hope that harnessing developmental mechanisms can restore nervous system functions following damage or disease.

Figure 1

Homeostatic control of synaptic strength by semaphorin-plexin signaling. (a) Retrograde Sema2b-PlexB signaling at the Drosophila neuromuscular junction regulates presynaptic glutamate release in response to changes in neuronal activity. Activation of the PlexB receptor in motor axons activates the cytosolic oxidoreductase Mical, which in turn depolymerizes actin to regulate neurotransmitter release via the readily releasable synaptic vesicle pool. (b) Increased neuronal activity induces secretion of Sema3F, which signals through an Nrp-2/PlexA3 holoreceptor complex to regulate cell surface AMPAR levels. This mechanism of homeostatic downscaling requires direct interaction between the CUB domains of Nrp-2 and GluA1, and also a functional PlexA3 RasGAP domain.

Figure 2

Cofilin regulates growth cone dynamics following injury. A conditioning peripheral nerve lesion promotes increased cofilin activity and actin turnover in conditioned afferent DRG projections. Following spinal cord injury, the severing activity of cofilin can sustain regeneration of conditioned DRG central afferent projections.