Remodeling of Axonal Connections Contributes to Recovery in an Animal Model of Multiple Sclerosis

Abstract

In multiple sclerosis (MS), inflammation in the central nervous system (CNS) leads to damage of axons and myelin. Early during the clinical course, patients can compensate this damage, but little is known about the changes that underlie this improvement of neurological function. To study axonal changes that may contribute to recovery, we made use of an animal model of MS, which allows us to target inflammatory lesions to the corticospinal tract (CST), a major descending motor pathway. We demonstrate that axons remodel at multiple levels in response to a single neuroinflammatory lesion as follows: (a) surrounding the lesion, local interneurons show regenerative sprouting; (b) above the lesion, descending CST axons extend new collaterals that establish a “detour” circuit to the lumbar target area, whereas below the lesion, spared CST axons increase their terminal branching; and (c) in the motor cortex, the distribution of projection neurons is remodeled, and new neurons are recruited to the cortical motor pool. Behavioral tests directly show the importance of these changes for recovery. This paper provides evidence for a highly plastic response of the motor system to a single neuroinflammatory lesion. This framework will help to understand the endogenous repair capacity of the CNS and to develop therapeutic strategies to support it.

The immunomodulator glatiramer acetate influences spinal motoneuron plasticity during the course of multiple sclerosis in an animal model

“…This hypothesis is based on the observation that, during the course of the disease, a series of plastic phenomena involving alpha motoneuron afferents correlate with a worsening of the symptoms of the disease (5). Also, a highly plastic response of the motor system after neuroinflammatory lesion was reported by Kerschensteiner et al (3), with axonal remodeling being observed at multiple levels, including the area surrounding the lesion, and above as well as inside the motor cortex (3).…”

“…During the course of EAE, damage to the axons as well as the occurrence of synaptic plasticity phenomena in the brain and spinal cord contribute to the clinical signs of the disease (3,6,7). Synaptic plasticity in the spinal cord may explain, at least in part, the rapid sensorimotor recovery of the animals soon after tetraplegia (3,5). In view of the importance of a better understanding of MS as well as its experimental models, major advances in understanding how cellular and humoral immune responses contribute to the pathogenesis of these diseases have been made in recent years (8)(9)(10)(11)(12).…”

“…Demyelination similar to that seen during the course of MS may be induced in animals, in a model called experimental autoimmune encephalomyelitis (EAE) (1)(2)(3)(4)(5). During the course of EAE, damage to the axons as well as the occurrence of synaptic plasticity phenomena in the brain and spinal cord contribute to the clinical signs of the disease (3,6,7). Synaptic plasticity in the spinal cord may explain, at least in part, the rapid sensorimotor recovery of the animals soon after tetraplegia (3,5).…”

Chronic relapsing experimental allergic encephalomyelitis (CREAE) in plasminogen activator inhibitor‐1 knockout mice: the effect of fibrinolysis during neuroinflammation

“…Growth-associated protein 43 (GAP-43) is an axonal phosphoprotein involved in regulating the growth state of axon terminals. These proteins have previously been studied in EAE and MS and used as indicators of neuronal damage and plasticity [24][25][26]. To obtain semiquantitative data regarding neuronal integrity and pathology, Western blotting for GAP-43 ( Figure 3iiA) and MAP2 (Figure 3iiB) was carried out on whole SCH samples from PAI-1 -/-and WT mice at different stages of CREAE.…”

Evaluation of corticospinal axon loss by fluorescent dye tracing in mice with experimental autoimmune encephalomyelitis

“…An earlier study demonstrated a 40-50% loss of CST axons at 90 and 180 days post-EAE induction via myelin-oligodendrocyte glycoprotein injection in C57/BL6 or Biozzi mice, and consistent a melioration of CST axon loss, spinal compound action potential amplitudes and areas, and clinical scores in phenytointreated animals (Black et al, 2006). In a CST local target EAE model, descending CST axons extend new collaterals above the lesion that establish a "detour" circuit to the lumbar target area, whereas below the lesion, spared CST axons increase their terminal branching (Kerschensteiner et al, 2004). The DiI tracer also is a competent candidate for monitoring such axonal restructuring in EAE model with axonal protective or repair-oriented treatment.…”