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

Mutations in the genes encoding the lysine demethylase 5 (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 presynaptically for neuroanatomical development and synaptic function. The Jumonji C (JmjC) domain-encoded histone demethylase activity of KDM5, which is expected to be diminished by many ID-associated alleles, is required for appropriate synaptic morphology and neurotransmission. The activity of the C5HC2 zinc finger is also required, as an ID-associated mutation in this motif reduces NMJ bouton number, increases bouton size, and alters microtubule dynamics. 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. [Display omitted] •Drosophila KDM5 regulates transcriptional programs vital to synaptic development•KDM5 uses demethylase-dependent and independent means to regulate NMJ development•The demethylase activity of KDM5 promotes bouton number and neurotransmission•The C5HC2 motif of KDM5 is needed for neuroanatomical development Mutations in the KDM5 family of histone demethylases are observed in individuals with intellectual disability (ID). Belalcazar et al. show that KDM5-regulated transcription is necessary in Drosophila for proper neuroanatomical development and neurotransmission at the glutamatergic larval neuromuscular junction.