DGKθ Catalytic Activity Is Required for Efficient Recycling of Presynaptic Vesicles at Excitatory Synapses

Synaptic transmission relies on coordinated coupling of synaptic vesicle (SV) exocytosis and endocytosis. While much attention has focused on characterizing proteins involved in SV recycling, the roles of membrane lipids and their metabolism remain poorly understood. Diacylglycerol, a major signaling lipid produced at synapses during synaptic transmission, is regulated by diacylglycerol kinase (DGK). Here, we report a role for DGKθ in the mammalian CNS in facilitating recycling of presynaptic vesi.cles at excitatory synapses. Using synaptophysin- and vGlut1-pHluorin optical reporters, we found that acute and chronic deletion of DGKθ attenuated the recovery of SVs following neuronal stimulation. Rescue of recycling kinetics required DGKθ kinase activity. Our data establish a role for DGK catalytic activity at the presynaptic nerve terminal in SV recycling. Altogether, these data suggest that DGKθ supports synaptic transmission during periods of elevated neuronal activity. Goldschmidt et al. identified a cellular role for the lipid kinase DGKθ in the mammalian brain. DGKθ was found to localize to excitatory synapses where its activity is required cell autonomously to promote efficient retrieval of synaptic vesicles following sustained neuronal activity.