Jing Zhang1,2,4 · Tianyao Liu2  · Zonghong Long1  · Zuoxi Wu1  · Jing Luo2  · Fuhai Bai1  · Lianyu Zhou2  · Hong Gong2  · Meifeng Gong2  · Hong Li1  · Xiaotang Fan2,3

1 Department of Anesthesiology, Second Affiliated Hospital of Army Medical University (Xinqiao Hospital), Chongqing 400038, China 

2 Department of Military Cognitive Psychology, School of Psychology, Army Medical University, Chongqing 400038, China 

3 Key Laboratory of Extreme Environmental Medicine, Ministry of Education, Chongqing 400038, China 

4 Department of Anesthesiology, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, China

Abstract

Ubiquinol cytochrome c reductase core protein I (UQCRC1) is a crucial subunit of Complex III, essential for its assembly. Reduced UQCRC1 expression impairs memory and spatial learning in mice, though the mechanisms are unclear. This study found that diminished UQCRC1 expression resulted in significant impairments in hippocampus-dependent cognition, which correlated with a notable decrease in UQCRC1 and synaptic proteins within the dentate gyrus (DG). RNA sequencing analysis of the hippocampus revealed a reduction in cilia, identified as a critical factor contributing to these cognitive deficits. Significantly, the overexpression of Ttbk2 in the DG restored ciliary function and mitigated cognitive impairments. Additionally, in vivo electrophysiological experiments demonstrated that theta and gamma rhythms and wide-wave interneuron reactivity in the hippocampus DG were present in Uqcrc1^+/- mice and could be rescued through Ttbk2 overexpression. These findings suggest that the downregulation of UQCRC1 expression contributes to cognitive decline by impairing neural oscillations and the functionality of wide-wave interneurons, likely due to ciliary damage.

Keywords

UQCRC1; Cognition; Dentate gyrus; Cilium

[SpringerLink]