Selective Ablation of Sod2 in Astrocytes Induces Sex-Specific Effects on Cognitive Function, d-Serine Availability, and Astrogliosis

• DOI: 10.1523/jneurosci.2543-21.2022
• Publication Date: 2022-06-27T17:50:18Z
• Authors: Matthew P. Baier; Raghavendra Y. Na...; Hannah P. Yarbrough; Daniel B. Owen; Anthony M. Masingale; Rojina Ranjit; Megan A. Stiles; Ashley Murphy; Martin-Paul Agbaga; Mohiuddin Ahmad; David M. Sherry; Michael T. Kinter; Holly Van Remmen; Sreemathi Logan
• Keywords: Astrogliosis; SOD2; Cognitive Decline

Cognitive decline is a debilitating aspect of aging and neurodegenerative diseases such as Alzheimer9s disease are closely associated with mitochondrial dysfunction, increased reactive oxygen species, neuroinflammation, astrogliosis. This study investigated the effects decreased antioxidant response specifically in astrocytes on cognitive performance neuronal function C57BL/6J mice using tamoxifen-inducible astrocyte-specific knockout manganese superoxide dismutase (aSOD2-KO), matrix that detoxifies generated during respiration. We reduced astrocyte SOD2 levels male female at 11–12 months age tested an automated home cage (PhenoTyper) apparatus for diurnal patterns, spatial learning, memory 15 age. aSOD2-KO impaired hippocampal-dependent working flexibility reversal phase testing paradigm males. Female showed no learning deficits compared age-matched controls despite significant reduction hippocampal expression. males further long-term potentiation, but paired-pulse facilitation was unaffected. Levels d-serine, NMDA receptor coagonist, were also mice, knockouts compensatory increase serine racemase Furthermore, demonstrated density astrocytes, indicative astrogliosis, hippocampus controls. These data demonstrate stress recapitulates age-related function, d-serine availability, Therefore, improving homeostasis may provide therapeutic target intervention impairment aging. <b>SIGNIFICANCE STATEMENT</b> Diminished astrogliosis disease. Manganese (SOD2) maintains homeostasis. show astrocytic ablation impairs plasticity memory, reduces potentiation neurons neuromodulator increases consistent defects advanced Our strong evidence sex-specific functions dysfunction.