Deficits in Adult Neurogenesis, Contextual Fear Conditioning, and Spatial Learning in aGfapMutant Mouse Model of Alexander Disease

Abstract

Glial fibrillary acidic protein (GFAP) is the major intermediate filament of mature astrocytes in the mammalian CNS. Dominant gain of function mutations in GFAP lead to the fatal neurodegenerative disorder, Alexander disease (AxD), which is characterized by cytoplasmic protein aggregates known as Rosenthal fibers along with variable degrees of leukodystrophy and intellectual disability. The mechanisms by which mutant GFAP leads to these pleiotropic effects are unknown. In addition to astrocytes, GFAP is also expressed in other cell types, particularly neural stem cells that form the reservoir supporting adult neurogenesis in the hippocampal dentate gyrus and subventricular zone of the lateral ventricles. Here, we show that mouse models of AxD exhibit significant pathology in GFAP-positive radial glia-like cells in the dentate gyrus, and suffer from deficits in adult neurogenesis. In addition, they display impairments in contextual learning and spatial memory. This is the first demonstration of cognitive phenotypes in a model of primary astrocyte disease.

Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nervous system

“…A clear example, showing that problems with the IF network can cause a disease, is Alexander disease, a lethal neurodegenerative disease with extensive reactive gliosis. In this disorder de novo mutations in GFAP lead to a pronounced white matter pathology [97] and the expression of mutant GFAP in a mouse model negatively affects neurogenesis and cognition [97,98].…”

The endocannabinoid system in guarding against fear, anxiety and stress

“…Interestingly, whereas the CB1R expressed at presynaptic terminals seems to reduce neurotransmitter release, the astroglial CB1R seems to potentiate synaptic glutamatergic signalling 133,134 . Considering that astroglial cells have been suggested to participate in anxiety, fear and stress-coping 136,137 , it will be interesting to assess whether similar astroglial CB1R-dependent mechanisms operate in the effect of cannabinoids and endocannabinoid signalling on these processes.…”

The Role of Glia in Stress

“…These show polarity and are in fact the stem cells of the developing brain. 13, 14,15,16 . Several morphologically distinct subtypes of RGCs in fetal macaque neocortex produce neurons and are guides for the migration of neural progenitors.…”