GfapMutation and Astrocyte Dysfunction Lead to a Neurodegenerative Profile with Impaired Synaptic Plasticity and Cognitive Deficits in a Rat Model of Alexander Disease

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Alexander disease (AxD) is a rare neurological disorder caused by dominant gain-of-function mutations in the gene for glial fibrillary acidic protein. Expression of mutant protein results in astrocyte dysfunction that ultimately leads to developmental delay, failure to thrive, and intellectual and motor impairment. The disease is typically fatal, and at present there are no preventative or effective treatments. To gain a better understanding of the link between astrocyte dysfunction and behavioral deficits in AxD, we have recently developed a rat model that recapitulates many of the clinical features of the disease, including failure to thrive, motor impairment, and white matter deficits. In the present study, we show that both male and female AxD model rats exhibit a neurodegenerative profile with a progressive neuroinflammatory response combined with reduced expression of synaptic and mitochondrial proteins. Consistent with these results, AxD rats show reduced hippocampal long-term potentiation and are cognitively impaired, as demonstrated by poor performance in the Barnes maze and novel object recognition tests. The AxD rat provides a novel model in which to investigate the impact of astrocyte pathology on central nervous system function and provides an essential platform for further development of effective treatments for AxD and potentially other neurodegenerative diseases with astrocyte pathology.