Brain-specific Drp1 regulates postsynaptic endocytosis and dendrite formation independently of mitochondrial division

Dynamin-related protein 1 (Drp1) divides mitochondria as a mechano-chemical GTPase. However, the function of Drp1 beyond mitochondrial division is largely unknown. Multiple Drp1 isoforms are produced through mRNA splicing. One such isoform, Drp1(ABCD), contains all four alternative exons and is specifically expressed in the brain. Here, we studied the function of Drp1(ABCD) in mouse neurons in both culture and animal systems using isoform-specific knockdown by shRNA and isoform-specific knockout by CRISPR/Cas9. We found that the expression of Drp1(ABCD) is induced during postnatal brain development. Drp1(ABCD) is enriched in dendritic spines and regulates postsynaptic clathrin-mediated endocytosis by positioning the endocytic zone at the postsynaptic density, independently of mitochondrial division. Drp1(ABCD) loss promotes the formation of ectopic dendrites in neurons and enhanced sensorimotor gating behavior in mice. These data reveal that Drp1(ABCD) controls postsynaptic endocytosis, neuronal morphology and brain function.