Targeted deletion in astrocyte intermediate filament (Gfap) alters neuronal physiology.

Abstract

Glial fibrillary acidic protein (GFAP) is a member of the family of intermediate filament structural proteins and is found predominantly in astrocytes of the central nervous system (CNS). To assess the function of GFAP, we created GFAP-null mice using gene One of the key events during astrocyte differentiation is the onset of expression of the intermediate filament glial fibrillary acidic protein (GFAP). Astrocyte precursors initially express vimentin, switching to GFAP as they mature (2, 3). Neurons make a similar switch from vimentin to the three neurofilaments during their differentiation (4). GFAP is considered a unique marker for astrocytes in the CNS, but it is also present in several other cell types in the periphery, particularly nonmyelinating Schwann cells of the peripheral nervous system (5-7). The levels of GFAP markedly increase during reactive gliosis when astrocytes undergo both hypertrophy and hyperplasia (for review see ref. 8). Recent studies of either forced overexpression or antisense inhibition of GFAP expression in cultured cells suggest a direct role for GFAP in controlling outgrowth of processes by astrocytes (9-11).Recently, two groups reported that targeted mutations in the Gfap gene do not interfere with mouse development (12,13). Preliminary studies of astrocyte numbers and morphology in these mice indicated little change, but morphology in particular has been difficult to assess in the absence of GFAP, which itself has been the standard marker for visualizing astrocytes at the light microscopic level. Upon injury, GFAPdeficient astrocytes appeared to initiate at least some of the molecular changes typical of reactive astrocytes. Given the many proposed interactions between astrocytes and neurons, changes in astrocyte structure or function might lead to changes in neuronal physiology. We have also generated GFAP-null mice using homologous recombination in embryonic stem (ES) cells. We report here that GFAP-null mice have subtle changes in astrocyte morphology, and in addition show enhanced long-term potentiation (LTP) in hippocampal neurons.

Astrocytes in Alzheimer's Disease

“…The obvious candidate is GFAP, which is increased in reactive astrocytes. Reduction of GFAP expression affects synaptic plasticity, 208,209 whereas increase in GFAP expression induces various forms of encephalopathy and alters synaptic activity. 168 Conceptually, levels of GFAP expression can be affected by steroid hormones 168 and even by caloric restriction.…”

Protection against Human Immunodeficiency Virus Type 1 Tat Neurotoxicity by Ginkgo biloba Extract EGb 761 Involving Glial Fibrillary Acidic Protein

“…Tat transgenic mice and GFAP-null mice were previously generated. 17,24 The GFAP-null mice used for these experiments are congenic in a C57BL/6J background. Combination GFAP-null/Tat mice were obtained by standard cross-breeding using a higher Tat-expressing line Tg 271.…”

Correlation of B-FABP and GFAP expression in malignant glioma

“…Studies using GFAP-null mice indicate no gross developmental abnormalities, suggesting that small amounts of other proteins such as vimentin may compensate for lack of GFAP (Gomi et al, 1995). However, recent studies suggest that GFAP is important for astrocytic-neuronal interactions because GFAP-null mice have alterations in long-term potentiation (or long-lasting enhancement of synaptic e cacy) in the hippocampus (McCall et al, 1996).…”