Yale researchers have found that a membrane lipid plays a crucial role in communicating information between synapses in the brain, according to a study published in Nature in September.

“This study is the first to show that lowering the levels of this lipid in nerve terminals affects the efficiency of neurotransmission,” said senior author Pietro De Camilli, M.D., FW ’79, the Eugene Higgins Professor of Cell Biology and a Howard Hughes Medical Institute investigator.

De Camilli and his team started by genetically engineering laboratory mice that lacked an enzyme, PIPK1-gamma, which in turn plays a role in synthesizing the lipid under investigation, phosphatidylinositol-4,5-bisphosphate—or PtdIns(4,5)P2—a member of a class of lipids called phosphoinositides. The mice born without PIPK1-gamma were apparently normal, but they were unable to feed and died quickly. Studies of their nervous systems revealed lower levels of PtdIns(4,5)P2 and a partial impairment both of the process of fusion of synaptic vesicles and of their recycling.

De Camilli’s laboratory has studied extensively the mechanism underlying cycling of synaptic vesicles, small sacs that contain neurotransmitters that exchange information between neurons. Synaptic vesicles release their contents at junctions between nerve terminals by fusing with the plasma membrane, where they rapidly reinternalize, reload with neurotransmitter and are reused.

These studies not only provide new insight into basic mechanisms in synaptic transmission, said De Camilli, a member of the Kavli Institute for Neuroscience at Yale, but also have implications for medicine. For example, Down syndrome patients have an extra copy of the gene encoding the enzyme synaptojanin 1, which degrades PtdIns(4,5)P2 in the brain. Patients with Lowe syndrome, who also have mental retardation, lack another PtdIns(4,5)P2-degrading enzyme. Cancer and diabetes also can result from abnormal metabolism of phosphoinositides, De Camilli said.

“Typically, studies of synaptic transmission have focused on membrane proteins,” he said. “Only recently has the importance of the chemistry of membrane lipids and of their metabolism started to be fully appreciated. The field is still in its infancy, but rapid advancements in the methodology for the analysis of lipids promise major progress in the field and the possibility of identifying new targets for therapeutic interventions in human diseases.”