Early loss of astrocyte p38α MAPK reduces hippocampal neuroinflammation, enhances synaptic strength, and increases non-synaptic mitochondrial uncoupling in female mice during non-pathological aging.

Abstract

The p38 mitogen-activated protein kinase has a well-characterized role in modulation of inflammatory processes throughout the body. In the central nervous system, p38 is primarily studied within neurons and microglia, most commonly in the context of neurological insult. The present study was designed to determine its function in astrocytes during non-pathological aging. We generated a conditional knockout model in which a tamoxifen-inducible Aldh1l1 promoter drives Cre recombinase expression in mice with exon 1 of the p38α gene flanked by loxP sites. Knockout of astrocyte p38α was achieved via tamoxifen administration in young sexually mature mice at 3-4 months old. Animals were subsequently aged to 21-24 months prior to performing electrophysiological, immunohistochemical, and biochemical analyses. We found that early loss of astrocyte p38α was associated with a reduction in hippocampal neuroinflammation and concomitant enhancement of synaptic strength in aged female mice. In subsequent experiments in younger animals, the knockout reduced peripheral GFAP levels and increased non-synaptic mitochondrial uncoupling. These findings indicate that astrocyte p38α has wide-ranging effects on brain metabolism, inflammation, and synaptic function during the course of normal aging, including release of GFAP from the central nervous system to the periphery. Follow-up studies exploring the role of astrocyte p38α in various age-associated neuropathological contexts are warranted.