Altered Brain Extracellular Matrix Structure and Sex-Specific Learning/Memory Dysfunction in Mice Lacking the Functional Amyloid Cystatin-Related Epididymal Spermatogenic

The brain's extracellular matrix (ECM) is highly specialized and unique. Unlike the collagen-rich matrices found in other tissues, it consists of complex proteoglycans and glycosaminoglycans that play critical roles in neuroplasticity including the integration and storage of new memories. Cystatin-related epididymal spermatogenic (CRES) is a member of a reproductive subgroup of family 2 cystatins and part of a specialized functional amyloid-containing ECM with host defense functions in the epididymal lumen. CRES and the endogenous epididymal amyloid matrix exhibit high plasticity, forming distinct amyloid structures, with antimicrobial functions tailored to specific bacterial strains. Recent studies show that CRES/CRES amyloid is also present in the mammalian brain ECM and suggest its inherent shape-shifting properties might contribute to neuroplasticity. In this study, we utilized a CRES knock-out (KO) mouse model to determine if the loss of CRES altered the structure of the hippocampal and cortical ECM and impacted brain function. We report that CRES KO male and female mice exhibited sex-specific structural changes in both the loose/interstitial and perineuronal net (PNN) ECM. Additionally, young CRES KO males-but not females-displayed deficits in learning, memory, and executive functioning when compared with WT controls. In contrast, older CRES KO males did not exhibit behavioral deficits, a finding that correlated with the observation of a similar PNN ECM structure when compared with WT mice. Our data suggest that CRES functions as a regulatory or structural component of the brain ECM, contributing to its sex-specific structural organization and plasticity, affecting sex-specific behaviors of learning and memory.