lowering levels of lipid in nerve terminals affects neurotransmission efficiency

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Study is the first to show that lowering the levels of lipid in nerve

terminals affects the efficiency of neurotransmission

Posted By: News-Medical in Medical Study News 26-Sep-2004

Yale researchers demonstrate the crucial role of a membrane lipid called

phosphatidylinositol-4,5-bisphosphate (PtdIns (4,5)P2) in the

communication of information between synapses in the brain, according to

a study published this week in Nature.

" 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, Eugene Higgins Professor of Cell

Biology and a Medical Institute investigator.

De Camilli's laboratory has extensively studied the mechanism underlying

cycling of synaptic vesicles, the small sacs containing

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 re-internalize,

reload with neurotransmitter, and are reused.

The researchers genetically engineered laboratory mice lacking the

enzyme PIPK1-gamma at the synapse. This enzyme plays a major role in the

synthesis of 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 system revealed lower levels of PtdIns(4,5)P2 and a partial

impairment both of the process of fusion of synaptic vesicles as well as

of their recycling.

De Camilli said these studies provide new insight into basic mechanisms

in synaptic transmission, 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, " said De Camilli. " 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. "

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