Don't get too excited: mechanisms of glutamate-mediated Purkinje cell death.
Purkinje cells (PCs) present a unique cellular profile in both the cerebellum and the brain. Because they represent the only output cell of the cerebellar cortex, they play a vital role in the normal function of the cerebellum. Interestingly, PCs are highly susceptible to a variety of pathological conditions that may involve glutamate-mediated 'excitotoxicity', a term coined to describe an excessive release of glutamate, and a subsequent over-activation of excitatory amino acid (NMDA, AMPA, and kainite) receptors. Mature PCs, however, lack functional NMDA receptors, the means by which Ca(2+) enters the cell in classic hippocampal and cortical models of excitotoxicity. In PCs, glutamate predominantly mediates its effects, first via a rapid influx of Ca(2+)through voltage-gated calcium channels, caused by the depolarization of the membrane after AMPA receptor activation (and through Ca(2+)-permeable AMPA receptors themselves), and second, via a delayed release of Ca(2+) from intracellular stores. Although physiological levels of intracellular free Ca(2+) initiate vital second messenger signaling pathways in PCs, excessive Ca(2+) influx can detrimentally alter dendritic spine morphology via interactions with the neuronal cytoskeleton, and thus can perturb normal synaptic function. PCs possess various calcium-binding proteins, such as calbindin-D28K and parvalbumin, and glutamate transporters, in order to prevent glutamate from exerting deleterious effects. Bergmann glia are gaining recognition as key players in the clearance of extracellular glutamate; these cells are also high in S-100beta, a protein with both neurodegenerative and neuroprotective abilities. In this review, we discuss PC-specific mechanisms of glutamate-mediated excitotoxic cell death, the relationship between Ca(2+) and cytoskeleton, and the implications of glutamate, and S-100beta for pathological conditions, such as traumatic brain injury.[1]References
- Don't get too excited: mechanisms of glutamate-mediated Purkinje cell death. Slemmer, J.E., De Zeeuw, C.I., Weber, J.T. Prog. Brain Res. (2005) [Pubmed]
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