The dark side of neuroplasticity

Abstract

Whether dramatic or modest, recovery of neurological function after spinal cord injury (SCI) is greatly due to neuroplasticity -the process by which the nervous system responds to injury by establishing new synaptic connections or by altering the strength of existing synapses. However, the same neuroplasticity that allows locomotor function to recover also produces negative consequences such as pain and dysfunction of organs controlled by the autonomic nervous system. In this review we focus specifically on structural neuroplasticity (the growth of new synaptic connections) after SCI and on the consequent development of pain and autonomic dysreflexia, a condition of episodic hypertension. Neuroplasticity after SCI is stimulated by the deafferentation of spinal neurons below the lesion and by the expression of growth-promoting neurotrophins such as nerve growth factor (NGF). A broad range of therapeutic strategies that affect neuroplasticity is being developed for the treatment of SCI. At one end of the spectrum are therapeutic strategies that directly or indirectly increase NGF in the injured spinal cord, and have the most robust effects on neuroplasticity. At the other end of the spectrum are neuroprotective strategies focused on supporting and rescuing uninjured, or partially injured, axons; these might limit the deafferentation stimulus for neuroplasticity. In the middle of this spectrum are strategies that block axon growth inhibitors without necessarily providing a growth stimulus. The literature supports the view that the negative consequences of neuroplasticity develop more commonly with therapies that directly stimulate nerve growth than they develop in the untreated injured cord. Compared to these conditions, neuroplasticity with negative outcomes is less prevalent after treatments that that neutralize axon growth inhibitors, and least apparent after strategies that promote neuroprotection.

An Engulfment Assay: A Protocol to Assess Interactions Between CNS Phagocytes and Neurons

“…Furthermore, while we have applied this protocol to visualize engulfment of synapses during developmental synaptic remodeling in the healthy CNS, this protocol can also be applied in disease models. In particular, this protocol can be used to study diseases in which synapses undergo substantial remodeling, such as in the case of synapse loss and regeneration following spinal cord injury, early synapse loss associated with Alzheimer's disease, etc 12,[14][15][16][17][18][19][23][24][25][26] . In addition, one may also adapt this technique to study diseases in which phagocytosis of material other than synapses has been described, such as microglia/macrophage-mediated engulfment of myelin in demyelinating disease (e.g., multiple sclerosis) and engulfment of beta-amyloid in Alzheimer's disease 5,6,[27][28][29] .…”

“…In addition to these roles in the healthy nervous system, synaptic remodeling is also involved in nervous system disease/injury 12,14,15 . For example, following spinal cord injury, severed axons must subsequently remodel and form new synapses to achieve functional recovery [16][17][18][19] .…”

Functional distinction between NGF-mediated plasticity and regeneration of nociceptive axons within the spinal cord

“…Hyperinnervation of these axons onto neurons within the deeper dorsal horn was thought to be one of the primary mechanisms by which NGF leads to the establishment of chronic pain (Christensen and Hulsebosch 1997b; Romero et al, 2001; Brown and Weaver, 2012). Indeed, we previously observed that co-application of Semaphorin 3A with NGF in uninjured rats was capable of reducing sprouting and mechanical hyperalgesia (Tang et al, 2004).…”

Life-span plasticity of the brain and cognition: From questions to evidence and back

“…Plasticity may be a response to rewarded behavior, a change in maintenance of previously acquired behaviors, or just a by-product of activity (Wolpaw, 1997). Plenty of examples illustrate the dark side of this potentially beneficial phenomenon: focal dystonia in musicians (Classen, 2003); tinnitus (Pantev et al, 2012), poor recovery from spinal cord injury (Brown and Weaver, 2012) are all laid at the feet of plasticity, and judging by the distribution of agerelated differences in the brain, regions that retain greater plasticity may also be especially prone to age-related vulnerability (Raz et al, 1997;2001). Thus, while the research efforts concentrate on finding ways to maintain and promote plasticity throughout the adult life span, more attention should be paid to unintended consequences of manipulation of plasticity in adulthood.…”