<i>Gfap</i>Mutation and Astrocyte Dysfunction Lead to a Neurodegenerative Profile with Impaired Synaptic Plasticity and Cognitive Deficits in a Rat Model of Alexander Disease

Alexander disease (AxD) is a rare neurological disorder caused by dominant gain-of-function mutations in the gene for glial acidic fibrillary protein (<i>GFAP</i>). 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 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.<b>Significance Statement</b> Alexander disease (AxD) is a fatal neurodegenerative disorder caused by gain-of-function <i>GFAP</i> mutations. We recently developed a <i>Gfap</i> ^+/R237H rat model which demonstrates hallmark astrocyte pathology, myelin deficits, and motor impairment. Here, we show that <i>Gfap</i> ^+/R237H rats also exhibit reduced synaptic plasticity and cognitive deficits as additional clinically relevant phenotypes, further demonstrating its utility as a model. Hippocampal transcriptomic analysis in young adult animals reveals a neurodegenerative signature with an innate immune response and loss of synaptic and metabolic gene expression, features that are typically associated with chronic diseases of aging. These results reveal mechanisms by which astrocyte dysfunction leads to learning and memory deficits in AxD and perhaps contributes to other diseases such as Alzheimer's and Parkinson's.