STRUCTURAL PLASTICITY OF THE ADULT CNS. NEGATIVE CONTROL BY NEURITE GROWTH INHIBITORY SIGNALS

Abstract

The neuronal network of the adult central nervous system (CNS) retains a limited capacity for growth and structural change. This structural plasticity has been best studied in the context of lesion-induced growth and repair. More recently, structural changes underlying functional plasticity occurring under specific physiological conditions have also been documented, in particular in the cortex and the hippocampus. Areas known for their adult plastic potential retain high levels of the growth associated protein GAP-43, suggesting a persistence of important components of the intracellular growth machinery throughout life. Interestingly, a pronounced negative correlation exists between the levels of GAP-43 and myelination in the adult CNS. Because CNS myelin contains potent neurite growth inhibitory membrane proteins, neurite growth, sprouting and plasticity were investigated in the spinal cord and brain in areas where oligodendrocyte development and myelin formation was experimentally prevented, or in the presence of an inhibitor neutralizing antibody (mAB-IN-1). In all areas, lesion-induced or spontaneous sprouting was enhanced, in parallel with persistent high levels of GAP-43. Thus, spontaneous sprouting of side branches occurred from retinal axons in the optic nerve in the absence of myelin, and target-deprived retinal axons showed increased sprouting and innervation of the contralateral optic tectum in the presence of mAB IN-1. In experimentally myelin-free spinal cords collaterals from intact dorsal roots grew over long distances to innervate deafferented target regions following the section of three dorsal roots. Similarly, the corticospinal tract sprouted across the the midline and re-established a dense plexus of fibres on the contralateral side of the spinal cord following section of one corticospinal tract in juvenile rats. Following bilateral dorsal hemisection of the spinal cord including both corticospinal tracts in young and adult rats, long distance regeneration of corticospinal fibres leading to significant functional improvements of locomotion and certain reflexes was induced by the neurite growth inhibitor neutralizing antibody IN-1.