title: Upregulation of calcium binding protein, S100A6, in activated astrocytes is linked to glutamate toxicity.
abstract: S100A6 (calcyclin), an EF-hand calcium binding protein, is considered to exert various functions, e.g., cell proliferation and differentiation, calcium homeostasis, and neuronal degeneration. In this study, we aimed to investigate whether S100A6 might be linked to glutamate toxicity using three animal models and pharmacological interventions. We first examined the age-related changes in S100A6 immunoreactivity in the mouse hippocampus, considering that an important negative aspect of brain aging is linked to increased extracellular glutamate. The surface area of S100A6-positive (+) astrocytes was significantly larger in aged mice than in young mice, while the numbers of S100β+ astrocytes did not change with age. In the second experiment, we examined the alterations in S100A6 immunoreactivity in the injured hypoglossal nucleus, because glutamate toxicity is considered to contribute to neuronal death after axotomy. There was no apparent S100A6 immunoreactivity in the hypoglossal nucleus of sham control animals. However, intense labeling for S100A6 in activated astrocytes was observed in the axotomized hypoglossal nucleus of mice. Administration of ceftriaxone, an astrocyte glutamate transporter enhancer, to axotomized mice significantly decreased the immunoreactivity for S100A6. In the third experiment, we tested an animal model of epilepsy using kainic acid (KA), a glutamate analog. In the mouse hippocampus after KA injection, S100A6 immunoreactivity was significantly increased in astrocytes, and pyknotic changes were observed in CA3 pyramidal neurons. Treatment of MK-801, an N-methyl-d-aspartate receptor antagonist, counteracted the KA-induced increase in S100A6 immunoreactivity, and reduced the numbers of pyknotic neurons. Our results indicate that upregulation of astrocytic S100A6 in response to extracellular glutamate may be involved in neuronal damage under pathophysiological conditions.
authors.affiliation: Department of Developmental Molecular Anatomy, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Yamada
authors.forename: S
authors.initials: S
authors.lastname: Jinno
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D019771:Axotomy; D056654:CA3 Region, Hippocampal / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002452:Cell Count; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D018698:Glutamic Acid / Q000633:toxicity*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D007002:Hypoglossal Nerve / Q000473:pathology; D007150:Immunohistochemistry; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D000075383:S100 Calcium Binding Protein A6; D009418:S100 Proteins / Q000096:biosynthesis*; D016707:Tissue Fixation; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018797:Cell Cycle Proteins; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D000075383:S100 Calcium Binding Protein A6; D009418:S100 Proteins; C489134:S100a6 protein, mouse; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D007608:Kainic Acid