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.
Slemmer
Jennifer E
JE
Department of Neuroscience, Erasmus Medical Center, Dr. Molenwaterplein 50, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
De Zeeuw
Chris I
CI
Weber
John T
JT
D000818:Animals; D016923:Cell Death / Q000502:physiology*; D002526:Cerebellar Diseases / Q000473:pathology* / Q000503:physiopathology*; D018698:Glutamic Acid / Q000502:physiology*; D006801:Humans; D009498:Neurotoxins; D011689:Purkinje Cells / Q000473:pathology* / Q000502:physiology
D009498:Neurotoxins; D018698:Glutamic Acid