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Neuronal plasticity can be described as the latent potential of the various components of the nervous system to act in response to environmental influences with adaptive alterations to neuronal structures. Neuronal plasticity consists of the ability of the nervous system to adapt its structural organization to new situations emerging from changes of developmental and environmental situations, as well as other factors such as disease or injury that affect the conditions of the nervous system. There are many neurodegenerative brain diseases known in man and is can be assumed that they all have a detrimental effect upon plasticity, however do plastic effects respond to disease or injury in a positive compensatory fashion or are all plastic effects victims of disease progression as are many other brain functions? One of the most studied neurodegenerative brain diseases is amyotrophic lateral sclerosis (ALS) due to the existence of animal models for the disease and the large amount of characterisation of the progression of the disease that has been carried out. Neuronal death or apoptosis is symptomatic of most human neurological disorders, including Alzheimer's, Parkinson's and Huntington's diseases, stroke, and ALS. The characterisation of specific genetic and environmental factors liable for these diseases has provided evidence for a pathway of neuronal death that involves oxidative stress, perturbed calcium homeostasis, mitochondrial dysfunction and activation of cysteine proteases called caspases. These neuronal death pathways are compensated for by plasticity based responses which suppress oxyradicals and stabilize calcium homeostasis and mitochondrial function (Mattson, 2000).
Alterations in Plasticity
There is a huge variety of methods for the enacting of neuronal plasticity by the neural system and I have brought together several papers that provide compelling evidence for the existence of such plasticity based systems in various cases of neurodegenerative disease or neural injury and alterations both positive and negative that occur in this conditions.
Mouse Models of ALS
The semaphorins are a class of proteins that act as axonal growth cone guidance molecules which are important in neural development. It has been shown that semaphorin 3A (Sema3A) expression in terminal Schwann cells is dependent upon the subtype of skeletal muscle fibers that the axons the terminal Schwann cells are associated with form neuromuscular junctions with. Specifically Sema3A levels are found to be increased in the terminal Schwann cells that are associated with axons that form neuromuscular junctions with fast-fatigable muscle fibers. Anatomical plasticity is therefore apparent in simulated cases of damage to these neuromuscular junctions and it would appear that Sema3A is involved in this process. However, in mice that have been bred to model ALS it has been shown that the expression of Sema3A actually suppresses plasticity effects at neuromuscular junctions and therefore may be involved in the early loss of neuromuscular junctions that is symptomatic of ALS (De Winter, et al., 2006). Mouse models of neurodegenerative brain diseases are very useful in determining the specific effects of these diseases and in trying to determine if there is any form of compensatory plasticity occurring in response to the effects of the disease. The superoxide dismutase (SOD1) mutation creates mice that demonstrate the phenotypic and histopathologic characteristics of human ALS. Using a further mutation of the SOD1 strain referred to as SOD1G93A, it has been shown that at the presymptomatic stage of development (approximately 60 days after birth) motor neurons extracted from SOD1G93A mice have upregulation of genes for transcriptional and translational functions, lipid and carbohydrate metabolism, mitochondrial pre-protein translocation and respiratory chain function. This could be evidence of a strong adaptive and possible plastic response to the effects of the SOD1G93A mutation. Mice 30 days past the presymptomatic stage still demonstrate upregulation of genes for carbohydrate metabolism however downregulation of genes for transcription and mRNA processing becomes apparent. Approximately 120 days after birth several negative effects are apparent, such as transcriptional repression, downregulation of several genes responsible for transcriptional and metabolic functions. However, some positive effects are still found, upregulation of complement system components and increased expression of important cyclins that are involved in the regulation of the cell-cycle. These multiple effects, both positive and negative are too complex to immediately assign them to be plasticity based responses to the onset of the effects of the SOD1G93A mutation, but they certainly indicate that some neuroprotective and possibly regenerative effects are occurring (Ferraiuolo, Heath, Holden, Kasher, Kirby, & Shaw, 2007). Specifically the corticostriatal synaptic plasticity of SOD1 mice and related strains has been examined by generating LTD in SOD1 mice by repetitive stimulation of the corticostriatal pathways. However, in SOD1G93A mice repetitive stimulation of the corticostriatal pathways generated an N-methyl-D-aspartic acid (NMDA) receptor dependent LTP, LTD could be restored in these mice through the addition of large amounts of dopamine or dopamine agonists. It would appear that the degeneration of dopaminergic neurons in the substantia nigra of SOD1G93A mice strains can cause significant alterations in corticostriatal synaptic plasticity (Geracitano, et al., 2003). Compensatory synaptic plasticity has been observed in the muscles and the central nervous system of motor neuron disease patients and SOD1 mice but evidence for this in spinal motor neurons has not yet been observed. There are five classes of presynaptic terminals of motor neurons (S, F, T, M, and C) and there have been recent observations of selective enlargements of C-type axon terminations that synapse with spinal motor neurons in the spinal cords of autopsied ALS patients. The synaptic terminations in transgenic SOD1G93A mice and wild type SOD1 mice were examined using computerized morphometry on electron micrographs to measure their appositional lengths, coverage of the motor neuron membrane, and sizes of postsynaptic structures. No degeneration of the terminals was observed in SOD1 mice but in SOD1G93A mice degeneration of motor neurons and S-terminals and F-terminals was observed but the C-terminals was preserved and in fact their appositional lengths and motor neuron coverage increased (Figure 1). This demonstrates selective preservation and increased presynaptic territory of the C-type terminal. C-terminals derive from cholinergic intrasegmental propriospinal interneurons and may modulate motor neuron excitability, therefore their amplified presynaptic territory on surviving motoneurons of SOD1 mice appears to demonstrate a plasticity based method for maintaining excitability and therefore compensating for the loss of presynaptic input (Pullen & Athanasiou, 2009).
Figure 1: Comparative frequency (A) and coverage (B) of the neuronal membrane of S-terminals, F-terminals and C-terminals in transgenic SOD1G93A mice. Data has been collected from six pairs of transgenic SOD1G93A mice at each age, and a pair of wild type SOD1 mice at 18 weeks, and expressed as Tg/Wt ratio (%). Between 10 and 18 weeks of age, S-terminals and F-terminals decline in frequency and coverage, but C-terminals show a maintained frequency and extended coverage. The proportional numbers (C) and proportional cover (D) of the neuronal membrane (B) both increase during disease progression. Values are mean Â± SEM. MN, motor neuron. *P < 0.05, **P < 0.01, ***P < 0.002. (Pullen & Athanasiou, 2009)
Simon et al (2010) Proximal spinal muscular atrophy (SMA) is caused by homozygous loss or mutation of the SMN1 gene on human chromosome 5. Depending on the levels of SMN protein produced from a second SMN gene (SMN2), different forms of the disease are distinguished. In patients with milder forms of the disease, type III or type IV SMA that normally reach adulthood, enlargement of motor units is regularly observed. However, the underlying mechanisms are not understood. Smn1/2 mice, a mouse model of type III/IV SMA, reveal progressive loss of motor neurons and denervation of motor endplates starting at 4 weeks of age. Loss of spinal motor neurons between 1 month and 12 months reaches 40%, whereas muscle strength is not reduced. In these animals, amplitude of single motor unit action potentials in the gastrocnemic muscle is increased more than 2-fold. Confocal analysis reveals pronounced sprouting of innervating motor axons. As ciliary neurotrophic factor (CNTF) is highly expressed in Schwann cells, we investigated its role for a compensatory sprouting response and maintenance of muscle strength in this mouse model. Genetic ablation of CNTF results in reduced sprouting and decline of muscle strength in Smn1/2 mice. These findings indicate that CNTF is necessary for a sprouting response and thus enhances the size of motor units in skeletal muscles of Smn1/2 mice. This compensatory mechanism could guide the way to new therapies for this motor neuron disease.
Vukosavic et al (2000) Molecular mechanisms of apoptosis may participate in motor neuron degeneration produced by mutant copper/zinc superoxide dismutase (mSOD1), the only proven cause of amyotrophic lateral sclerosis (ALS). Consistent with this, herein we show that the spinal cord of transgenic mSOD1 mice is the site of the sequential activation of caspase-1 and caspase-3. Activated caspase-3 and its produced b-actin cleavage fragments are found in apoptotic neurons in the anterior horn of the spinal cord of affected transgenic mSOD1 mice; although such neurons are few, their scarcity should not undermine the potential importance of apoptosis in the overall mSOD1-related neurodegeneration. Overexpression of the anti-apoptotic protein Bcl-2 attenuates neurodegeneration and delays activation of the caspases and fragmentation of b-actin. These data demonstrate that caspase activation occurs in this mouse model of ALS during neurodegeneration. Our study also suggests that modulation of caspase activity may provide protective benefit in the treatment of ALS, a view that is consistent with our recent demonstration of caspase inhibition extending the survival of transgenic mSOD1 mice.
Wright et al (2007) Loss of synaptic activity or innervation induces sprouting of intact motor nerve terminals that adds or restores nerve-muscle connectivity. Ciliary neurotrophic factor (CNTF) and terminal Schwann cells (tSCs) have been implicated as molecular and cellular mediators of the compensatory process. We wondered if the previously reported lack of terminal sprouting in CNTF null mice was due to abnormal reactivity of tSCs. To this end, we examined nerve terminal and tSC responses in CNTF null mice using experimental systems that elicited extensive sprouting in wildtype mice. Contrary to the previous report, we found that motor nerve terminals in the null mice sprout extensively in response to major sprouting-stimuli such as exogenously applied CNTF per se, botulinum toxin-elicited paralysis, and partial denervation by L4 spinal root transection. In addition, the number, length and growth patterns of terminal sprouts, and the extent of reinnervation by terminal or nodal sprouts, were similar in wildtype and null mice. tSCs in the null mice were also reactive to the sprouting-stimuli, elaborating cellular processes that accompanied terminal sprouts or guided reinnervation of denervated muscle fibres. Lastly, CNTF was absent in quiescent tSCs in intact, wildtype muscles and little if any was detected in reactive tSCs in denervated muscles. Thus, CNTF is not required for induction of nerve terminal sprouting, for reactivation of tSCs, and for compensatory reinnervation after nerve injury. We interpret these results to support the notion that compensatory sprouting in adult muscles is induced primarily by contact-mediated mechanisms, rather than by diffusible factors.
Brain Activation in ALS Patients
The use of functional magnetic resonance imaging (fMRI) to examine the activation states of the brain during various tasks is a very powerful tool in the search for plastic cortical reorganisation effects in the cases of brain disease and injury. Using simple and difficult motor tasks we can examine the differences in activation states between ALS patients and healthy subjects (Schoenfeld, et al., 2005).
Reorganisation of cortical structures in response to brain damage can be thought of as a collection of many plasticity based responses. When the brain activation patterns of ALS patients was compared to those of healthy subjects it was observed that a very different but distinctive pattern of activation was found in the ALS patients as compared to the healthy volunteers. Essentially activation was found in areas of the brain functionally related to those affected by the progression of ALS, for example increased activation levels were found in the premotor gyrus, an area of the brain usually associated with the initiation and planning of movement as opposed to the controlling of actual movement (Figure 2). These finding demonstrate a consistent pattern of cortical reorganisation in ALS patients that may be indicative of a consistent set of plasticity based responses to the specific from of motor neuron degeneration caused by the progression of ALS (Konrad, et al., 2002).
Figure 2: Cortical activation during right hand movement in ALS patients (red) and healthy subjects (blue). Cortical activation of each group is shown using the radiological convention of right image side is the left hemisphere. The two top left slices show activation of the SMA and contralateral premotor area only in ALS patients (red). On the two top right slices, activation of healthy controls is noted (blue). ALS patients show larger SMA activation, more anterior activation in the SMA and premotor area and activation of the ipsilateral motor cortex. Interestingly there is a gap of activation over the depth of the central sulcus in patients with degeneration of motor neurons (top right slice and bottom left slice), but overall activation of the area encompassing the contralateral central sulcus is the same in ALS patients and controls (bottom slices). (Konrad, et al., 2002)
The cortical structures used in motor imagery, the mental process by which an individual rehearses or simulates a given action a process often used in neurological rehabilitation, are so similar to those cortical structures used for actual motor activity that they can substitute for the motor activity cortical structures in patients suffering from diseases or brain injury that affect these areas of the brain. Studying the progressive motor neuron degeneration in ALS patients and how it affects the use of cortical structures for motor imagery has shown that ALS patients have much higher levels of activation in areas of the brain responsible for motor imagery and control and that motor imagery tasks activated motor control areas. These alterations in cortical maps persisted after approximately 6 months demonstrating an ongoing compensatory plastic effect within the higher order motor-processing system of ALS patients (Kraft, et al., 2007).
De Winter, F., Vo, T., Stam, F. J., Wisman, L. A., Bar, P. R., Niclou, S. P., et al. (2006). The expression of the chemorepellent Semaphorin 3A is selectively induced in terminal Schwann cells of a subset of neuromuscularsynapses that display limited anatomical plasticity and enhanced vulnerability in motor neuron disease. Mol. Cell. Neurosci. , 32, 102-117.
Ferraiuolo, L., Heath, P. R., Holden, H., Kasher, P., Kirby, J., & Shaw, P. J. (2007). Microarray Analysis of the Cellular Pathways Involved in the Adaptation to and Progression of Motor Neuron Injury in the SOD1 G93A Mouse Model of Familial ALS. The Journal of Neuroscience , 27 (34), 9201-9219.
Geracitano, R., Paolucci, E., Prisco, S., Guatteo, E., Zona, C., Longone, P., et al. (2003). Altered long-term corticostriatal synaptic plasticity in transgenic mice overexpressing human Cu/Zn superoxide dismutase (Gly93>Ala) Mutation. Neuroscience , 118, 399-408.
Goldberg, J. L., & Barres, B. A. (2000). Nogo in nerve regeneration. Nature , 403, 369-370.
Konrad, C., Henningsen, H., Bremer, J., Mock, B., Deppe, M., Buchinger, C., et al. (2002). Pattern of cortical reorganization in amyotrophic lateral sclerosis: a functional magnetic resonance imaging study. Exp Brain Res , 143, 51-56.
Kraft, E., Lulé, D., Diekmann, V., Kassubek, J., Kurt, A., Birbaumer, N., et al. (2007). Cortical Plasticity in Amyotrophic Lateral Sclerosis: Motor Imagery and Function. Neurorehabilitation and Neural Repair , 21, 518-526.
Mattson, M. P. (2000). Apoptosis in neurodegenrative disorders. Nature , 1, 120-129.
Pullen, A. H., & Athanasiou, D. (2009). Increase in presynaptic territory of C-terminals on lumbar motoneurons of G93A SOD1 mice during disease progression. European Journal of Neuroscience , 29, 551-561.
Schoenfeld, M. A., Tempelmann, C., Gaul, C., Kühnel, G. R., Düzel, E., Hopf, J.-M., et al. (2005). Functional motor compensation in amyotrophic lateral sclerosis. Journal of Neurology , 252, 944-952.
Simon, C. M., Jablonka, S., Ruiz, R., Tabares, L., & Sendtner, M. (2010). Ciliary neurotrophic factor-induced sprouting preserves motor function in a mouse model of mild spinal muscular atrophy. Human Molecular Genetics , 1-14.
Vukosavic, S., Stefanis, L., Jackson-Lewis, V., Guegan, C., Romero, N., Chen, C., et al. (2000). Delaying Caspase Activation by Bcl-2: A Clue to Disease Retardation in a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis. The Journal of Neuroscience , 20 (24), 9119-9125.
Wright, M. C., & Son, Y.-J. (2007). Ciliary neurotrophic factor is not required for terminal sprouting and compensatory reinnervation of neuromuscular synapses: Re-evaluation of CNTF null mice. Experimental Neurology , 205, 437-448.