Excitotoxic lesioning of the rat basal forebrain with S-AMPA: consequent mineralization and associated glial response

Oliveira, Alcyr; Hodges, Helen and Rezaie, Payam (2003). Excitotoxic lesioning of the rat basal forebrain with S-AMPA: consequent mineralization and associated glial response. Experimental Neurology, 179(2) pp. 127–138.

DOI: https://doi.org/10.1016/S0014-4886(02)00012-2

Abstract

Regional depositions of calcium within the basal ganglia, cortex, cerebellum, and white matter and at perivascular sites have been observed in several pathological conditions. These generally indicate signs of ongoing apoptosis or necrotic processes, whereby the activation of glutamate receptors causes a rise in intracellular calcium levels leading to mineralization of neurons, and ultimately to cell death. The selective degeneration of cholinergic neurons in the basal forebrain is a major neuropathological component of Alzheimer's disease, and may result in abnormal deposition of calcium. In experimental models, selective lesions of the basal forebrain can be induced by intraparenchymal infusions of excito- or immunotoxins targeting cholinergic neurons. Excitotoxic lesions are often accompanied by calcium deposition within affected areas. In a previous study we also noted the presence of unusual deposition in areas close to the site of injections following unilateral S-AMPA-induced lesions of the basal forebrain (T. Perry, H. Hodges, and J. A. Gray, 2001, Brain Res. Bull. 54, 29-48). In this paper, we have characterized these deposits histologically and evaluated the microglial (CD11b) and astrocytic (GFAP) responses at 8 and 16 weeks following lesioning of the nucleus basalis magnocellularis with S-AMPA. The resulting deposits were heterogeneous in morphology and composed primarily of calcium. Small granular deposits were detected around blood vessels, whereas larger calcospherites were situated within the parenchyma. These deposits were more widely dispersed at 16 weeks postlesioning, affected neighboring nuclei, and displayed a progressive increase in size and frequency of occurrence. However, calcification within these regions was differentially associated with microglial and astrocytic reactivity at the two time points. Both microglial and astrocytic responses were pronounced at 8 weeks, whereas at 16 weeks, astrocytic reactivity prevailed and the microglial response was markedly attenuated. Importantly, the pattern of reactivity for microglia detected at 8 weeks was specifically localized to vulnerable nucleated areas prior to their substantial accumulation of calcium deposits, which was clearly evident by 16 weeks. We suggest that the initial microglial response could be used as a selective predictor of tissue necrosis and subsequent calcification, and that astrocytes, which form a glial scar in the affected tissues, may contribute toward the buildup of calcium deposits. The functional relevance of these findings is discussed.

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