Overproduction of hydrogen sulfide, generated by cystathionine β-synthase, disrupts brain wave patterns and contributes to neurobehavioral dysfunction in a rat model of down syndrome.

Using a novel rat model of Down syndrome (DS), the functional role of the cystathionine-β-synthase (CBS)/hydrogen sulfide (HS) pathway was investigated on the pathogenesis of brain wave pattern alterations and neurobehavioral dysfunction. Increased expression of CBS and subsequent overproduction of HS was observed in the brain of DS rats, with CBS primarily localizing to astrocytes and the vasculature. DS rats exhibited neurobehavioral defects, accompanied by a loss of gamma brain wave activity and a suppression of the expression of multiple pre- and postsynaptic proteins. Aminooxyacetate, a prototypical pharmacological inhibitor of CBS, increased the ability of the DS brain tissue to generate ATP in vitro and reversed the electrophysiological and neurobehavioral alterations in vivo. Thus, the CBS/HS pathway contributes to the pathogenesis of neurological dysfunction in DS, most likely through dysregulation of cellular bioenergetics and gene expression.