MINOCYCLINE PREVENTS PREMATURE COGNITIVE DECLINE IN A MOUSE MODEL OF INTELLECTUAL DISABILITY INDUCED BY ZBTB18/RP58 HAPLOINSUFFICIENCY

Abstract Transcriptional repressor ZBTB18/RP58 haploinsufficiency, consisting of heterozygous ZBTB18/RP58 missense and truncated variants, causes intellectual disability. However, the pathogenesis of intellectual disability and whether this disorder can be prevented or treated are unknown. Heterozygous Zbtb18/Rp58 knockout mice were used as a model of ZBTB18/RP58 haploinsufficiency. Multiple behaviors and local potentials were assessed, and histochemical analyses in the hippocampus was performed to assess microglial status and DNA fragmentation. Object location memory was similar in wild-type mice at 2 and 4-5-months-old mice, but it decreased at 12-18-months-old mice. In contrast, in Zbtb18/Rp58 heterozygous knockout mice, object location memory at 2-months-old was similar to that of age-matched wild-type mice but decreased at 4-5-months-old. In Zbtb18/Rp58 heterozygous knockout mice, DNA damage accumulation and activation of microglia in the dentate gyrus increased early, associated with defects in DNA repair. In particular, in Zbtb18/Rp58 heterozygous knockout mice, chronic administration of minocycline suppressed age-related phenotypes such as accumulation of DNA damage and impaired object location memory. In conclusion, Zbtb18/Rp58 heterozygous knockout mice exhibit early onset of cognitive decline related to defects in DNA repair, and minocycline suppressed this abnormality, suggesting that minocycline may be a potential therapeutic agent for cognitive dysfunction caused by ZBTB18/Rp58 haploinsufficiency.