Excitotoxic lesioning of the rat basal forebrain with S-AMPA: consequent mineralization and associated glial response Alcyr Oliveira, a, * Helen Hodges, a,b and Payam Rezaie c a Department of Psychology, Institute of Psychiatry, King’s College London, DeCrespigny Park, London SE5 8AF, UK b ReNeuron Ltd., 10 Nugent Road, Surrey Research Park, Guildford, Surrey GU2 7AF, UK c Department of Neuropathology, Institute of Psychiatry, King’s College London, DeCrespigny Park, London SE5 8AF, UK Received 3 May 2002; revised 19 September 2002; accepted 1 October 2002 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. © 2003 Elsevier Science (USA). All rights reserved. Keywords: Calcium deposits; Basal ganglia calcification; Microglia; Astrocytes Introduction Outside the central nervous system (CNS), the patholog- ical deposition of calcium is often linked with irreversible injury (for example, following myocardial ischemia), and has been best described as part of the process associated with atherosclerotic lesions, where calcium is gradually deposited in granular form and progressively accumulates around arterial walls (Stary, 2000, 2001). Within the central nervous system, mineralized calcium deposits are a feature associated with several neuropathological disorders includ- ing Alzheimer’s disease, certain inflammatory conditions, and experimental models of hypoxic-ischemic and excito- toxic injury (Table 1). The basal ganglia is known to demonstrate vulnerability under various pathological situations. The globus pallidus, in particular, is frequently the site of bilateral idiopathic * Corresponding author. E-mail address: spjtaao@iop.kcl.ac.uk (A. Oliveira). R Available online at www.sciencedirect.com Experimental Neurology 179 (2003) 127–138 www.elsevier.com/locate/yexnr 0014-4886/03/$ – see front matter © 2003 Elsevier Science (USA). All rights reserved. PII: S0014-4886(02)00012-2