AIDS-Related Dementia and Calcium Homeostasis. Xanya Sofra Weiss

STUART A. LIFTON

Our laboratory has a long-standing interest in the relationship of neuronal viability and outgrowth to intracellular Ca2+ levels (reviewed in ref. 1). Glutamate, or a related excitatory amino acid (EAA), is the major excitatory neurotransmitter that controls the level of intracellular neuronal Ca"Our laboratory has a long-standing interest in the relationship of neuronal viability and outgrowth to intracellular Ca2+ levels (reviewed in ref. 1). Glutamate, or a related excitatory amino acid (EAA), is the major excitatory neurotransmitter that controls the level of intracellular neuronal Ca2+([Ca2+]i). Escalating concentrations of glutamate have been measured in vivo following focal stroke and head injury (reviewed in refs. 2 and 3). As a result, there is a rapid rise in [Ca2+]i CaZtli may not account by itself for the ensuing neuronal injury, several laboratories have now reported that prevention of the increase in [Ca2+]i Jlie ads to amelioration of anticipated neuronal cell death (reviewed in refs. 2 and 3). Excessive intracellular Ca2+ is thought to contribute to the triggering of a series of potentially neurotoxic events leading to cellular necrosis orperhaps apoptosis. Many mechanisms are involved in intracellular calcium homeostasis, and this subject is beyond the scope of this article (but see the review in ref. 4).Here we will consider only two modes of Caz+ entry into neurons during these pathological processes. These two routes of entry of Ca2+o ccur via ion channels that are permeable to Ca2+ and can be summarized as follows: (1) Glutamate or related EAAs trigger voltage-dependent calcium channels by depolarizing the cell membrane; a major voltage-dependent calcium channel subtype that is chronically activated by prolonged depolarizations is the L-type calcium channel (reviewed in ref. 5). (2) Glutamate or related EAAs activate ligand-gated ion channels directly; a predominant glutamate receptor-operated channel that is permeable to Ca2+ under these conditions is the Nmethyl-D-aspartate (NMDA) subtype, but other non-NMDA types may also contribute (reviewed in refs. 2 and 6). We have shown that activation of these channel types can control neuronal plasticity during normal development, but our laboratory and many others have shown that in excessive amounts this stimulation can lead to neuronal death, for example, after a stroke (reviewed in ref. 1). Similar mechanisms may obtain in various neurodegenerative conditions. In fact, although not involved in the primary pathophysiology of a neurologic disorder, this mechanism may represent a final common pathway of neuronal injury. Most importantly, this pathway makes the disease process amenable to pharmacotherapy. This line of reasoning led us to think that this mechanism might be involved in acquired immunodeficiency syndrome (AIDS)-related neuronal injury.

Xanya Sofra Weiss

Xanya Sofra Weiss