Prenatal Stress Is Associated With a Sex-Specific Camkii Modulation in Aged Mouse Prefrontal Cortex

Abstract Animal evidence has suggested that prenatal stress programs sex-specific trajectories of brain aging; however, the molecular correlates of these trajectories in the aged prefrontal cortex (PFC) have remained undisclosed. Previous report shows that unpredictable chronic mild stress (UCMS) applied to C57BL/6J dams during gestation, followed by fragmented maternal care, produced in male offspring a progression from midlife anhedonia to hyperlocomotion, reduced avoidance and spatial memory deficits at 18 months, whereas female offspring developed late-onset anhedonia with preserved hippocampus-dependent memory. Herein, proteomic LC-MS/MS was used to investigate the prefrontal cortex (PFC) of 18-month-old C57BL/6J offspring exposed to UCMS protocol. CaMKIIα and CaMKIIβ showed opposite stress-associated changes between sexes. An exploratory postsynaptic module comprising CaMKII isoforms and IQSEC1/2 increased in females and decreased in males, with a significant sex-by-stress interaction, corroborated by Western blotting. In males, mitochondrial aspartate aminotransferase (GOT2) was the most robust individual change, accompanied by increased phosphorylated tau and AKT. Females exhibited increased CaMKII abundance alongside reduced phosphorylation ratios and additional neuropeptidergic, bioenergetic, and neuroimmune candidates. These findings suggest sex-dependent molecular adaptations in the aged PFC following prenatal stress.