Targeting neural cell senescence reverses neuropsychiatric disorders

The accumulation of senescent cells behaves as a key driver of several age-related cancers and degenerative diseases of the general population. Whether cellular senescence also contributes to psychiatric diseases is still elusive. We report here the characterization of a zebrafish model of psychiatric disorder resulting from the invalidation of the ppp2r2c gene known to be involved in various psychiatric pathologies in human and encoding a neural specific regulatory subunit of the Protein Phosphatase 2A (PP2A). We found that the behavioral abnormalities of adult ppp2r2c-defficient fish were associated to neural cell senescence and that they can be reversed by invalidating the tp53 gene or by treating the fish with a drug that eliminates senescent cells. A molecule commonly used to treat ADHD patients, the methylphenidate, decreases the number of senescent neural cells both in adult PPP2R2C-defficient fish and in wild-type old fish. At the molecular level, methylphenidate attenuates the DNA damage response. We propose that some of the drugs commonly used in neuropsychiatry such as methylphenidate can prevent the appearance of senescent neural cells and that general strategies to clear senescent cells are promising therapies for common psychiatric disorders. RNA-Seq of zebrafish brain was performed using HiSeq X Ten, in two biological replicates for vehicle groups (a4 and WT) and three biological replicates for treated groups (MpH and Val).