Lesioning of the inferior olive using a ventral surgical approach. Characterization of temporal and spatial astrocytic responses at the lesion site and in cerebellum.

Activated astrocytes, intrinsic components of both local and remote (axonal target regions) central nervous system injury responses, are now recognized as active metabolic and regulatory mediators in many neurological disorders. To further define these responses, we devised a new ventral surgical approach to unilaterally lesion the inferior olivary nuclear complex, which has a single predominant remote target, the cerebellum. Activated astrocyte number, volume, and density, as well as the total volume of brainstem involved in the astrocytic response, all peaked at postlesion day (pld) 4, returning toward, but not to, unoperated control values at pld 24 (p < 0.05). In contrast, the peak astrocyte response in the cerebellum was delayed, being greatest at pld 6 (p < 0.05 compared to control or pld 2). These responses were associated with increases in overexpression of S100 beta, an astrocyte-derived neurite growth factor, and with an increase in cerebellar steady-state levels of a neuronal injury response protein, the beta-amyloid precursor protein (beta-APP). This is similar to correlated increases in these two proteins that are found in epilepsy and Alzheimer disease. Our studies defining remote astrocytic and neuronal responses may be important for understanding glial-neuronal mechanisms underlying the spread of neuropathological changes in conditions such as Alzheimer disease.