Intermediate filaments in astrocytes

Abstract

Astrocytes, a prominent cell type in the brain, are receiving more and more attention from many neuroscientists. Astrocytes undergo a rather enigmatic process of activation in many pathological situations affecting the brain or spinal cord. These include CNS trauma, stroke, brain tumors or neurodegenerative diseases. A hallmark of astrocyte activation is upregulation of intermediate filaments (IFs), a part of the cytoskeleton. IFs are made of many IF proteins depending on the cell type, cell activation status and developmental stage of the organism. The role of IFs in unchallenged or reactive astrocytes has been unknown.To study the role of astrocytic IFs in normal and pathological conditions, we have utilized mice deficient in astrocytic IF proteins, glial fibrillary acidic protein (GFAP) and/or vimentin. Combined biochemical, morphological and ultrastructural analyses of astrocytes from these mice allowed us to define the partnership rules for astrocytic IF proteins.GFAP-/-vimentin-/- mice are devoid of astrocytic IFs in reactive astrocytes in vivo and in vitro. GFAP-/-vimentin-/- mice exhibited impaired glial scar formation following brain or spinal cord injury. This points to upregulation of astrocytic IFs as a crucial event in the process of astrocyte activation. Two in vitro studies offered potential explanation for the above finding. GFAP-/- astrocytes were incapable of inducing blood-brain barrier properties in endothelial cells, and the absence of IFs led to a major defect in astrocyte motility. The latter finding suggests regulation of cell motility as a new function for IFs. IF-free astrocytes were also found to respond abnormally to hypotonic stress, a condition resembling cytotoxic edema in stroke, which implies the role of IFs in astrocyte volume regulation.