DEK Loss Induces Task-specific Deficits in Learning and Memory and Reprograms the Hippocampal Transcriptome in Mice.

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• DEK is an estrogen-responsive protein in the brain, crucial for memory-related regions like the hippocampus.
• DEK loss is linked to Alzheimer's disease (AD) cellular features, with expression declining in women with dementia severity.
• Previous studies suggest a sex-specific link between DEK and cognitive vulnerability, but in vivo consequences were unknown.

Purpose of the Study:

• To investigate the behavioral and molecular effects of DEK loss in male and female mice.
• To determine the functional role of DEK in cognitive, sensorimotor, and affective domains.
• To explore sex-specific consequences of DEK deficiency in the brain.

Main Methods:

• Generated constitutive knockout (cKO) mice lacking the Dek gene in both sexes.
• Assessed cognitive flexibility, spatial learning, memory, locomotor activity, anxiety, and sensorimotor gating.
• Conducted transcriptomic profiling of hippocampal tissue to identify molecular changes.

Main Results:

• Dek cKO mice of both sexes showed normal locomotor activity, anxiety, sensorimotor gating, and fear memory.
• Female Dek cKO mice exhibited impaired cognitive flexibility, unlike males, indicating female-specific vulnerability.
• Transcriptomic analysis revealed shared and sex-specific molecular alterations in Dek-deficient hippocampi, affecting neuronal signaling and chromatin regulation.

Conclusions:

• DEK loss has sex- and cognitive-domain-specific effects, particularly impacting cognitive flexibility in females.
• Findings highlight a potential neuroprotective role for DEK, especially in female cognitive function.
• Further research on DEK's role in executive function and hippocampal-prefrontal cortex circuitry is warranted.