My lab is interested in understanding the functions of the KDM5 (lysine demethylase 5) family of transcriptional regulators that act by binding to, and enzymatically modifying, chromatin. Specifically, I will be talking about our efforts to define how mutations in kdm5 genes cause heritable forms of syndromic and non-syndromic intellectual disability in humans. To do this, we are utilizing the genetic toolkit available by using the model organism Drosophila. In addition to examining the effects of loss of KDM5 function using a null mutation, we are leveraging the fact that all 19 disease-associated missense mutations affect evolutionarily conserved residues. These mutations do not cluster in a particular domain of KDM5, thus it is unknown whether they alter similar or distinct target genes and pathways to affect cognition. To date, we have generated nine fly strains harboring intellectual disability-associated missense mutations and have begun defining the transcriptional, behavioral and cellular defects of these alleles. Our data reveal striking learning and memory defects that occur with or without altering neuronal morphology. Transcriptome analyses of these alleles also identify a cohort of overlapping genes that are likely to be key to the relationship between KDM5 and neuronal (dys)function.