Selective recognition memory impairment in mitochondrial hydroxylase Clk1 mutant mice, rescued by antipsychotics.

Mitochondria are not only the most important organelles in eukaryotic cells that participate in energy metabolism, signal transduction, cell apoptosis and other physiological processes, but also essential regulators of neurodevelopment, neuroplasticity, survival and adult neurogenesis. The mitochondria-localized hydroxylase Clk-1 is involved in ubiquinone biosynthesis. Recent evidence shows that Clk1 mutant mice are resistant to morphine- and methamphetamine-induced conditioned place preference. Given the critical role of learning and memory in drug dependence, we herein explored whether and how Clk1 deficiency affected the cognitive processes in mice. We found that mutant Clk1 mice (Clk1) exhibited recognition memory impairment in novel object recognition (NOR) and novel arm recognition (NAR) tests. In addition, we observed in Clk1 mutant mice a selective reduction in dendritic spine density in prefrontal cortex (PFC) but not in the hippocampus (HIP). The expression of brain-derived neurotrophic factor (BDNF) was also decreased in PFC but not in HIP. Furthermore, Clk1 mutant mice displayed impairment in the ERK/CREB signaling pathway in PFC that might underlie Clk1 mutation-induced changes in BDNF and dendritic morphology. Administration of antipsychotic drugs aripiprazole (0.3 mg·kg·d, i.p.) or risperidone (1 mg·kg·d, i.p.) for 7 days fully rescued Clk1 mutation-induced recognition memory deficits. This study provides primary evidence highlighting the role of mitochondrial Clk1 in the regulation of recognition memory and presents an informative model for investigating mitochondrial function in learning and memory.