ZBTB21 suppresses CRE-mediated transcription to impair synaptic function in Down syndrome

Down syndrome (DS) is the most common chromosomal disorder and a major cause of intellectual disability. The genetic etiology of DS is the extra copy of chromosome 21 (HSA21)-encoded genes; however, the contribution of specific HSA21 genes to DS pathogenesis remains largely unknown. Here, we identified ZBTB21, an HSA21-encoded zinc-finger protein, as a transcriptional repressor in the regulation of synaptic function. We found that normalization of the Zbtb21 gene copy number in DS mice corrected deficits in cognitive performance, synaptic function, and gene expression. Moreover, we demonstrated that ZBTB21 binds to canonical cAMP-response element (CRE) DNA and that its binding to CRE could be competitive with CRE-binding factors such as CREB. ZBTB21 represses CRE-dependent gene expression and results in the negative regulation of synaptic plasticity, learning and memory. Together, our results identify ZBTB21 as a CRE-binding protein and repressor in cAMP-dependent gene regulation, contributing to cognitive defects in DS.