Minocycline prevents early age-related cognitive decline in a mouse model of intellectual disability caused by ZBTB18/RP58 haploinsufficiency

Abstract

Abstract Transcriptional repressor ZBTB18/RP58 haploinsufficiency, which comprises heterozygous ZBTB18/RP58 missense and truncating variants, causes intellectual disability. However, the mechanism responsible for the onset of intellectual disability, and whether this disorder can be prevented and treated, are unknown. We focused on changes in cognitive function about adulthood in intellectual disability. Heterozygous Zbtb18/Rp58-knockout mice were used as a model for ZBTB18/RP58 haploinsufficiency. We assessed multiple behaviors and local field potential, examined DNA fragmentation and mitochondrial morphology, and performed histochemical analysis and transcriptome analysis in the hippocampus to evaluate chronic inflammation. Object location memory assessed by an object location test in wild-type mice was the same in 2 and 4–5-month-old mice, but it was impaired in 12–18-month-old mice. By contrast, object location memory in 2-month-old Zbtb18/Rp58 heterozygous-knockout mice was similar to that in age-matched wild-type mice but was impaired by 4–5-months of age, indicating the early onset of impaired spatial memory in the mutant mice. Zbtb18/Rp58 heterozygous-knockout mice exhibited early onset of DNA damage accumulation and an increment of activated microglia in the dentate gyrus that was associated with defective DNA repair. Because dementia is an established comorbidity in persons with intellectual disability, mutant mice may have mimicked not only delay of cognitive function but also an acquired cognitive impairment. Notably, chronic minocycline therapy, which has neuroprotective and anti-inflammatory effects, attenuated age-related phenotypes, such as accumulation of DNA damage, an increase of microglial activation and impairment of object location memory, in Zbtb18/Rp58 heterozygous-knockout mice. In conclusion, Zbtb18/Rp58 heterozygous-knockout mice showed early onset of cognitive decline caused by inflammation with a defect in DNA repair. Minocycline prevented early-onset cognitive decline, suggesting that it could have potential as a therapeutic agent for the treatment of ZBTB18/RP58 haploinsufficiency-associated cognitive dysfunction.