Don’t get too excited: mechanisms of glutamate-mediated Purkinje cell death

• Published in: Creating Coordination in the Cerebellum Vol. 148; pp. 367 - 390
• Main Authors: Slemmer, Jennifer E., De Zeeuw, Chris I., Weber, John T.
• Format: Book Chapter Journal Article
• Language: English
• Published: United Kingdom Elsevier Science & Technology 01.01.2005
• Subjects: Animals; Bergmann glia; Cell Death - physiology; Cerebellar Diseases - pathology; Cerebellar Diseases - physiopathology; cytoskeleton; dendritic spines; excitotoxicity; GLAST; Glutamic Acid - physiology; Humans; Internet guides & online services; microtubules; Neurology & clinical neurophysiology; Neurosciences; Neurotoxins; Purkinje Cells - pathology; Purkinje Cells - physiology; S-100β; traumatic brain injury; PF: parallel fiber; NO: nitric oxide; RAGE: receptor for advanced glycation end-products; mGluR: metabotropic glutamate receptor; DLB: dendritic lamellar body; LTD: long-term depression; NF: neurofilament; microtubules; trans-ACPD: trans-(±)-1-amino1,3-cyclopentanedicarboxylic acid; NMDA: N-methyl-D-aspartate; dendritic spines; CNQX: 6-cyano-7-nitroquinoxaline-2,3-dione; nNOS: neuronal nitric oxide synthase; PIP2: phosphatidylinositol bisphosphate; IP3: inositol-(1,4,5)-trisphosphate; GLAST; EAAT: excitatory amino acid transporter; [Ca2+]i: intracellular free calcium; MAP: microtubule-associated protein; PSD: postsynaptic density; CBP: Ca2+-binding protein; BG: Bergmann glia; IO: inferior olive; PC: Purkinje cell; CLIP-115: cytoplasmic linker protein of 115 kDa; excitotoxicity; PLC: phospholipase C; AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate; CLIP-170: cytoplasmic linker protein of 170 kDa; DCD: dark cell degeneration; GLAST: glutamate-aspartate transporter; PKC: protein kinase C; cytoskeleton; NBQX: 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo-(F)-quinoxaline; S-100β; traumatic brain injury; MT: microtubule; VGCC: voltage-gated calcium channel; DAG: diacylglycerol; LTP: long-term potentiation; ER: endoplasmic reticulum; CNS: central nervous system; CF: climbing fiber; TBI: traumatic brain injury; Bergmann glia
• ISBN: 9780444517548; 0444517545
• ISSN: 0079-6123; 1875-7855
• DOI: 10.1016/S0079-6123(04)48029-7

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 Ca2+ enters the cell in classic hippocampal and cortical models of excitotoxicity. In PCs, glutamate predominantly mediates its effects, first via a rapid influx of Ca2+through voltage-gated calcium channels, caused by the depolarization of the membrane after AMPA receptor activation (and through Ca2+-permeable AMPA receptors themselves), and second, via a delayed release of Ca2+ from intracellular stores. Although physiological levels of intracellular free Ca2+ initate vital second messenger signaling pathways in PCs, excessive Ca2+ influx can detrimentally alter dendritic spine morphology via interactions with the neuronal cytoskeleton, and thus can perturb normal synaptic function. PCs possess various calcium-bining 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 clearence of extracellular glutamate; these cells are also high in S-100β, 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 Ca2+ and cytoskeleton, and the implications of glutamate, and S-100β for pathlogical conditions, such as traumatic brain injury.