Importantly, we demonstrate that the three chemical chaperones 4-phenylbutyrate, sorbitol, and trehalose are able to stabilize Munc18-1 protein levels, reversing the insolubility and aggregation of mutant Munc18-1, and to rescue neuronal deficits in vitro and in vivo, providing a novel therapeutic approach for Munc18-1-associated encephalopathies. Here, STXBP1 is linked to Encephalopathy.