engleski

Lesion-induced plasticity in the central nervous system

Neuronal death and subsequent denervation of target areas are hallmarks of many neurological disorders including brain trauma, ischemia and neurodegeneration (Alzheimer's disease). In response to this loss of innervation, denervated neurons retract and remodel their dendritic tree. The central nervous system responds to deafferentation by means of plastic remodeling processes, in particular by inducing outgrowth of new axon collaterals from surviving neurons (collateral sprouting). These sprouting processes result in a partial reinnervation, new circuitry, and functional changes within the deafferented brain regions. Although this appears to be a fundamental neuropathological process, the functional relevance of these dendritic alterations and their impact on neuronal electrical properties are poorly understood. The biological phenomenon of denervation-induced plasticity has been receiving more and more attention. It is now well recognized that the structural reorganization of neurons can contribute to disease pathogenesis as well as to functional regeneration following a partial injury. Dendritic retraction and remodeling are widely seen in neurological diseases and are usually considered signs of pathology and malfunction. In fact, some authors have even linked progressive impairment of dendrite maintenance to cognitive defects. One of the classical model system used to study lesion-induced plasticity is the reorganization of the hippocampal dentate gyrus following entorhinal cortex lesion (ECL). In this experimental setting entorhinal afferents to dentate granule cells are lost and granule cells profoundly remodel their dendritic tree. Using morphometric analysis of Thy1-GFP mice we recently documented these changes in neuronal arborization and showed that ECL results in protracted and long-term structural alterations of mouse granule cells. These changes occur in spite of collateral sprouting of surviving afferent fibers, suggesting that the spontaneously occurring reinnervation of granule cells is insufficient to maintain the granule cell arbor. Based on these experimental data, we also studied the electrotonic structure and excitability of denervated dentate granule cells. By retracting their dendritic trees, neurons receive a smaller number of synaptic inputs. The resulting reduced neuronal response is precisely compensated by an increase in synaptic potentials due to the smaller dendritic trees. This structural plasticity serves as a homeostatic mechanism that precisely maintains input-output firing relations. Our study provides a useful morphological baseline for further studies on dendritic denervation processes in vivo, in particular for studies using different mouse mutants.

entorhinal lesion; sprouting; Alzheimer's disease; regeneration

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