Modulation of calcineurin signaling during development.

Calcineurin signaling pathways are suppressed in Down syndrome (trisomy 21), by overexpression of genes that are located on chromosome 21. Two key genes are the regulator of calcineurin 1 (RCAN1), also called the Down syndrome critical region 1 (DSCR1), and the dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A). The suppressed calcineurin pathway may potentially be restored using small-molecule DYRK inhibitors, which have been proposed as therapeutics in Down syndrome. However, little is known about the benefits and risks of such treatments during various stages of embryonic development, fetal development, and childhood. We examined the modulation of calcineurin signaling during development, using zebrafish as a model system. To mimic suppressed calcineurin signaling in Down syndrome, zebrafish were exposed to the calcineurin inhibitors cyclosporine and tacrolimus during development. We found that suppression of calcineurin signaling changed specific larval behaviors, including activity and responses to acoustic and visual stimuli, depending on the period of exposure. Cotreatment with the DYRK inhibitor proINDY restored a few of these behaviors but also induced a range of adverse side effects including decreased activity and reduced optomotor responses to visual stimuli. Based on these results, we conclude that proINDY has limited benefits and substantial risks when used during development. We propose that zebrafish is an efficient model system for preliminary safety and efficacy tests of other DYRK inhibitors that aim to restore calcineurin signaling during neural development.