Early loss of astrocyte p38alpha MAPK has sexually dimorphic impacts on measures of neuronal excitability and cytokines in aged mice

Abstract

AbstractBackgroundThe p38alpha MAPK (p38) signaling pathway is ubiquitously expressed in the brain where it plays central roles in neuroinflammation, metabolism, synaptic development and communication, and modulation of blood brain barrier integrity. Its activity in astrocytes has largely been described as immunomodulatory; however, it has also recently been reported to contribute to long term depression and associated behaviors. Astrocytes are also known to be important to healthy brain aging and neuroprotection, but the specific involvement of astrocytic p38 signaling is unclear. We therefore used conditional KO mice to determine how the loss of p38 in astrocytes early in adulthood (3 months) affects synaptic function and cytokine expression phenotypes in later life (20+ months).MethodMice were bred homozygous for floxed p38, heterozygous for a Rosa reporter, and with or without tamoxifen‐inducible Cre recombinase under control of the astrocyte aldh1l1 promoter. When animals were about 3 months of age they were placed on tamoxifen diet (400 ppm) for 4 weeks, after which they were returned to standard chow and allowed to age until 20‐24 months prior to undergoing electrophysiological endpoints or collection of brain tissue for biochemical analyses. Electrically evoked field excitatory post synaptic potentials (fEPSPs) were recorded in hippocampal CA1 stratum radiatum in acutely prepared brain slices and cytokines from the whole hippocampus were measured from a subset of mice that did not undergo electrophysiological recordings.ResultMales and females showed baseline differences in measures of I/O, fiber volley amplitude, early vs. late potentiation, and paired pulse facilitation. Additionally, knockout of astrocyte p38 generally had opposite effects on these parameters in males and females. Interestingly, the pattern of hippocampal IL‐1β cytokine levels mirrored these differences.ConclusionThese data indicate that there may be qualitative differences in male versus female brain aging that are differentially impacted by astrocyte p38 signaling. The implications of these findings are currently being explored to determine the underlying mechanisms for these sexually dimorphic effects and further determine what functional differences may exist for hippocampal‐dependent behaviors.