Brpf1 Haploinsufficiency Impairs Neural Plastitiy,Leading To Cognitive Deficits

Intellectual disability is a common neurodevelopmental disorder characterized by impaired intellectual and adaptive functioning.Both environmental insults and genetic defects contribute to the etiology of intellectual disability.Bromodomain and PHD finger-containing protein 1(BRPF1)has been demonstrated to act as a multivalent chromatin reader,forming complexes with histone acetyltransferases,to stimulate acetyltransferase activity.Haploinsufficiency of BRPF1 gene causes intellectual disability(ID),however,the neurological basis for ID and the neurological function of BRPF1 dosage in the brain remain unclear.Here,by crossing Emx1-cre mice with Brpf1~fl/fll/fl mice,we generated Brpf1 heterozygous mice to model BRPF1-related ID.Brpf1 heterozygotes showed reduced dendritic complexity in both hippocampal granule cells and cortical pyramidal neurons,accompanied by reduced spine density and altered spine and synapse morphology.An in vitro study of Brpf1haploinsufficiency also demonstrated decreased frequency and amplitude of miniature EPSCs that may subsequently contribute to abnormal behaviors,including decreased anxiety levels and defective learning and memory.Our results demonstrate a critical role for Brpf1 dosage in neuron dendrite arborization,spine morphogenesis and behavior and provide insight into the pathogenesis of BRPF1-related ID.