Dek Loss Induces Sex-Dependent, Task-Specific Cognitive Deficits and Reprograms the Hippocampal Transcriptome in Mice

Cognitive decline with aging, and some neurodegenerative conditions like Alzheimer's disease, disproportionately affects females yet few mechanisms beyond steroid hormone signaling fully explain this sex-specific vulnerability. The chromatin-remodeling DEK protein, upregulated by estrogen and progesterone and broadly expressed in the brain, including the hippocampus, may be one such mechanism. We have previously linked DEK loss with indices of neuronal dysfunction, including increased DNA damage, impaired neurite development, and apoptosis, suggesting a potential neuroprotective role. Here, we investigated the molecular and behavioral consequences of Dek loss in vivo. Female Dek constitutive knockout (cKO) mice exhibited a sex-specific behavioral phenotype, with impairments in sensorimotor gating, as measured by pre-pulse inhibition, and in reversal learning in the Morris Water Maze. These findings are suggestive of deficits in pre-attentive sensory processing and cognitive flexibility, respectively. Notably, these cognitive deficits were not observed in male Dek cKO mice and were not attributable to differences in general learning ability, locomotor activity, or anxiety-like behavior. The absence of impairment in object recognition and conditioned fear learning and memory in females suggests that the effects of DEK loss are task-specific and likely brain region-specific. Transcriptomic analysis of hippocampal tissue revealed differentially expressed genes related to inflammation, metabolism, and neuropeptide signaling in all Dek-cKO mice, along with a distinct female-specific transcriptomic profile indicative of impaired neuronal function. Combined, we report for the first time that DEK supports certain aspects of cognitive function, particularly in females. These data may be relevant for understanding sex differences in some cognitive disorders.