Review
Myelin associated inhibitors: A link between injury-induced and experience-dependent plasticity

https://doi.org/10.1016/j.expneurol.2011.06.006Get rights and content

Abstract

In the adult, both neurologic recovery and anatomical growth after a CNS injury are limited. Two classes of growth inhibitors, myelin associated inhibitors (MAIs) and extracellular matrix associated inhibitors, limit both functional recovery and anatomical rearrangements in animal models of spinal cord injury. Here we focus on how MAIs limit a wide spectrum of growth that includes regeneration, sprouting, and plasticity in both the intact and lesioned CNS. Three classic myelin associated inhibitors, Nogo-A, MAG, and OMgp, signal through their common receptors, Nogo-66 Receptor-1 (NgR1) and Paired-Immunoglobulin-like-Receptor-B (PirB), to regulate cytoskeletal dynamics and inhibit growth. Initially described as inhibitors of axonal regeneration, subsequent work has demonstrated that MAIs also limit activity and experience-dependent plasticity in the intact, adult CNS. MAIs therefore represent a point of convergence for plasticity that limits anatomical rearrangements regardless of the inciting stimulus, blurring the distinction between injury studies and more “basic” plasticity studies.

Introduction

Spinal cord injuries (SCIs) have classically been regarded as devastating injuries from which there is no recovery due to restricted axonal growth in the adult central nervous system (CNS). This notion has been modified in recent years by reports of limited recovery in patients suffering from a variety of SCIs (Burns et al., 1997, Geisler et al., 2001). Understanding the basis of recovery, as well as the systems that limit growth in the CNS, has been the goal of a century of research. While our understanding remains incomplete, myriad studies have described how injured neurons can be stimulated to grow, overcome physical and chemical barriers, and make functional connections. Here we focus on studies demonstrating the role of myelin-associated inhibitors (MAIs) in restricting axonal growth in the CNS with particular emphasis on the Nogo–Nogo Receptor axis.

Pioneering work demonstrated that MAIs inhibit axonal regeneration; however, their physiological role remained unclear. Importantly, when MAIs have been antagonized in animal models of SCI, functional recovery exceeds frank axonal regeneration per se. The search for an anatomical correlate to increased functional recovery led to the insight that MAIs limit a wide spectrum of injury-induced growth that includes axonal regeneration, sprouting, and plasticity. Genetic dissection of the roles played by MAIs in SCI led to two important insights. First, SCI recovery is dependent on both regenerative and non-regenerative anatomical growth, significantly complicating our analysis of neurological recovery from CNS damage. Second, the existence of an inhibitory system regulating a wide spectrum of growth emphasizes the physiological role of MAIs, and led to the appreciation of a common regulatory system for both experience and activity-dependent plasticity. The existence of a shared system for limiting anatomical reorganization in the naïve and injured CNS blurs the distinction between translational injury repair studies and more “basic” plasticity studies.

Section snippets

Axonal regeneration

Regeneration is a remarkable feat that requires extensive coordinated biology: the lesioned axon must survive, find permissive cues for growth, receive appropriate trophic support, extend towards relevant synaptic targets, and ultimately make functional connections. Cajal first described the ability of PNS (peripheral nervous system), but not CNS, neurons to regenerate in 1928 (Cajal, 1991). Despite this early observation, nearly 60 years passed before a clear picture emerged as to why

Regeneration, sprouting, and plasticity: a continuum of repair

A wide spectrum of inhibitors has been observed to limit neurite outgrowth in vitro, and when antagonized in animal models of SCI, cause significant regeneration of severed axons in vivo. Nonetheless, the extent of the observed regeneration alone does not explain the levels of functional recovery observed in rodent and primate models of SCI. In classic spinal hemisection models targeting the corticospinal tract in rodents and primates, significant neurological recovery is observed despite scant

Myelin and plasticity in the naïve brain

The search for inhibitors of CNS regeneration led to the discovery of MAIs that limit a wide spectrum of injury-induced anatomical growth. Injury, however, is not the only stimulus for plasticity. The understanding that MAIs limit a wide spectrum of injury-induced anatomical plasticity led investigators to test if this system also limits plasticity in the uninjured CNS. It has now been demonstrated that MAIs limit both experience and activity dependent plasticity in the adult mammalian brain,

Injury, plasticity, and MAIs

The potential for recovery after a SCI is limited by the inhibitory environment of the mature CNS. The identification of these inhibitors and their receptors has led to the understanding that regeneration is a point along a continuum of anatomic growth that includes sprouting and plasticity. This spectrum represents distinct but fundamentally related forms of cytoskeletal rearrangements; the principle difference is magnitude. Given their demonstrated roles in regulating cytoskeletal dynamics (

Acknowledgments

F.A. is supported by an Institutional Medical Scientist Training Program from the N.I.H, NIH MSTP TG 2T32GM07205. This work was supported by the grants from the Christopher and Dana Reeve Foundation, the Wings for Life Foundation and the Dr. Ralph and Marion Falk Medical Research Trust to S.M.S., and from the National Institutes of Health to W.B.J.C. and S.M.S.

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    Disclosure: S.M.S. is a co-founder of Axerion Therapeutics seeking to develop PrP and NgR therapies.

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