Sex-dependent behavioral responses and phenotypic traits of Pcsk9 knockout mice in anxiety- and depression-like paradigms.

Abstract

Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) regulates plasma LDL cholesterol by promoting the degradation of LDL receptors. Beyond lipid metabolism, PCSK9 has been implicated in neuropsychiatric conditions, including depression and anxiety, potentially through mechanisms involving inflammation, insulin resistance, and hormonal regulation. This preclinical study investigated the effects of Pcsk9 deficiency on anxiety- and depression-like behaviors in male and female C57BL/6 mice, with additional analysis of corticosterone levels and the estrous cycle in females, taking advantage of the Pcsk9 knock-out (Pcsk9 KO) mouse model. Regardless of sex, Pcsk9 KO mice showed increased anxiety-like behavior, with reduced time and fewer entries into the open arms of the Elevated Plus Maze (p&#x202f;<&#x202f;0.0001), and less time in the light compartment of the Light-Dark Box Test (p&#x202f;<&#x202f;0.001). Exploratory behavior was greater in females than in males across genotypes. In the Open Field Test, Pcsk9 KO females traveled shorter distances and at lower speeds than WT females (p&#x202f;<&#x202f;0.01), while within Pcsk9 KO mice only, males were more active than females (p&#x202f;<&#x202f;0.05). In both sexes, Pcsk9 KO mice showed increased immobility in the Tail Suspension and Forced Swim Tests (p&#x202f;<&#x202f;0.05), and elevated grooming in the Splash Test (p&#x202f;<&#x202f;0.05). Estrous cycle analysis revealed that Pcsk9 KO females spent more time in estrus (p&#x202f;<&#x202f;0.0001) and less (p&#x202f;=&#x202f;0.0083) in diestrus than WT females, suggesting altered hormonal regulation. However, corticosterone levels did not significantly differ between groups. These findings indicate that, in a murine model of Pcsk9 deficiency, this loss may associate with sex-dependent emotional dysregulation, thus supporting further preclinical and clinical investigations into its neuropychiatric relevance.