The histone demethylase KDM5 is required for synaptic structure and function at the Drosophila neuromuscular junction

Abstract

Mutations in the genes encoding the KDM5 family of histone demethylases are observed in individuals with intellectual disability (ID). Despite clear evidence linking KDM5 function to neurodevelopmental pathways, how this family of proteins impacts transcriptional programs to mediate synaptic structure and activity remains unclear. Using the Drosophila larval neuromuscular junction (NMJ), we show that KDM5 is required for neuroanatomical development and synaptic function. The JmjC-domain encoded histone demethylase activity of KDM5, which is expected to be diminished by many ID-associated alleles and required for appropriate synaptic morphology and neurotransmission. The C5HC2 zinc finger of KDM5 is also involved, as an ID-associated mutation in this motif reduces NMJ bouton number but increases bouton size. KDM5 therefore uses demethylase-dependent and independent mechanisms to regulate NMJ structure and activity, highlighting the complex nature by which this chromatin modifier carries out its neuronal gene regulatory programs.