HINT1 deficiency in aged mice reduces anxiety-like and depression-like behaviours and enhances cognitive performances.

Abstract

Histidine triad nucleotide-binding protein 1 (HINT1) is regarded as a haplo-insufficient tumour suppressor and is closely associated with many neuropsychiatric disorders, including major depressive disorders. In addition, HINT1 knockout (KO) mice exhibit anxiolytic-like behaviour, antidepression-like behaviour, and enhanced cognitive performance in several studies. However, it is still unclear whether aging contributes to these changes in the emotion and cognition of HINT1 KO mice. This study examined the role of aging in anxiety-like and depression-like behaviours and cognition behaviours in aged HINT1 KO mice compared with young HINT1 KO mice and their wild-type littermates, along with a number of molecular biological methods. In a battery of behavioural tests, aged wild-type mice showed increased anxiety-like and depression-like behaviours and decreased cognitive performance, along with lower expression levels of glutathione peroxidase, enhanced amount of malondialdehyde, and decreased expression levels of brain-derived neurotrophic factor and tyrosine kinase B in the hippocampus and PFC compared to young wild-type mice. HINT1 KO mice showed reduced anxiety-like and depression-like behaviours and enhanced cognitive performance compared to age-matched wild-type mice. In addition, HINT1 KO mice also showed increased GSH-Px and superoxide dismutase, and decreased malondialdehyde, together with enhanced BDNF and Trk-B expression in the hippocampus and PFC. However, when compared with young HINT1 KO mice, aged HINT1 KO mice did not show increased anxiety-like and depression-like behaviours. And there are no differences in the expression level of superoxide dismutase, malondialdehyde, BDNF, and Trk-B between aged and young HINT1 KO mice. In summary, HINT1 deficiency can counteract age-related emotion and cognition dysfunction.