Today's knowledge on the temporally and spatially specific modulations of plasticity-associated genes and proteins (Table 9.1 and 9.2) implies two important aspects for a better understanding of the mechanism of adult plasticity. Firstly, the molecular response of the LPZ at 14 days post-lesion is different, as compared to earlier or later time points. Ca++/Calmodulin dependent protein kinase II alpha only showed significantly elevated levels of autophoshorylation 14 days after the induction of retinal lesions (Van den Bergh et al., 2003a). Similarly, the impact of retinal lesions on AMPA-type glutamate receptor subunit expression was also most intense after a 14 day-recuperation period, but nevertheless present form 3 to 30 days post-lesion (Van Damme et al., 2002). Related data on extracellular fluid glutamate levels and the expression of glial high-affinity Na+/K+-dependent glutamate transporters suggested a shift in the mechanism that controls the activation of glutamate receptors, from a differential synthesis/release of glutamate to a differential re-uptake (Massie et al., 2003a). Likewise, Obata and colleagues (1999) reported an effect of retinal lesions on neurotrophins in two waves, one starting a few days after lesioning and ending at 1 month, and a second one from 3 months to more than two years post-lesion. What mediates this wave-like feature of the molecular effects of retinal lesions is not yet clear and calls for more applied research to define the exact molecular mechanisms of cortical plasticity. The understanding of the exact sequence of different mechanisms could prove useful for the development of novel approaches for rehabilitation after central or peripheral lesions of the nervous system based on goal-directed pharmacological interventions to boost the recovery capacity intrinsically present in sensory cortex.
Secondly, we established that the cortical reorganization after retinal lesioning is certainly also driven by molecular changes occurring outside the LPZ, i.e. in remote non-deprived cortex (Qu et al., 2000, 2003, Massie et al., 2003a,b). Every neurotransmitter and neuromodulator that was investigated showed clearly increased levels in regions of area 17 devoted to peripheral vision as compared to control regions in normal animals (Table 9.1). The effect on extracellular fluid glutamate and GABA levels in remote area 17 turned out to increase with post-lesion survival time. The pronounced increase in glutamate could point to hyperexcitability and hyperactivity in remote visual cortex. The observation that also all the neuromodulatory systems were upregulated hints to a similar conclusion. Noradrenaline levels were specifically augmented, and as discussed by Pinaud (2000, 2004), nora-drenergic input to the visual cortex regulates light-induced zif268 expression. Therefore a quantitative investigation of the temporal and spatial modulations of zif268 and c-fos expression in the visual cortex should deliver final and conclusive evidence for the reaction of the complete visual cortex to limited retinal lesions. An ongoing modification of the physiological state and the function of non-deprived visual cortex appear necessary to allow functional reorganization of the cortical circuitry. Ample evidence indicates that also after brain damage a profound reorganization occurs in the spared cerebral cortex, as a contribution to recovery. Reorganizational effects take place at perilesional sites but also in remote cortical regions and even in the contralateral hemisphere, and may be driven by reciprocal intracortical connections. Such remote effects on the brain as a whole following restricted cortical lesions suggest a different contribution of distinct perilesional areas to the process of recovery and compensation for lost functions (Eysel et al., 1999; Keyvani et al., 2002; Frost et al., 2003; Reinecke et al., 2003).
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