Synaptic defects and compensatory regulation of inositol metabolism in inositol polyphosphate 1-phosphatase mutants

Neuron. 1998 Jun;20(6):1219-29. doi: 10.1016/s0896-6273(00)80502-4.


Phosphoinositides function as important second messengers in a wide range of cellular processes. Inositol polyphosphate 1-phosphatase (IPP) is an enzyme essential for the hydrolysis of the 1-phosphate from either Ins(1,4)P2 or Ins(1,3,4)P3. This enzyme is Li+ sensitive, and is one of the proposed targets of Li+ therapy in manic-depressive illness. Drosophila ipp mutants accumulate IP2 in their system and are incapable of metabolizing exogenous Ins(1,4)P2. Notably, ipp mutants demonstrate compensatory upregulation of an alternative branch in the inositol-phosphate metabolism tree, thus providing a means of ensuring continued availability of inositol. We demonstrate that ipp mutants have a defect in synaptic transmission resulting from a dramatic increase in the probability of vesicle release at larval neuromuscular junctions. We also show that Li+ phenocopies this effect in wild-type synapses. Together, these results support a role for phosphoinositides in synaptic vesicle function in vivo and mechanistically question the "lithium hypothesis."

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Chromosome Mapping
  • Cloning, Molecular
  • Drosophila / enzymology
  • Drosophila / genetics*
  • Electrophysiology
  • Female
  • Gene Expression Regulation, Enzymologic / physiology
  • Inositol Phosphates / metabolism*
  • Lithium / pharmacology
  • Male
  • Molecular Sequence Data
  • Mutation / physiology
  • Neurons / drug effects
  • Neurons / enzymology
  • Neurotransmitter Agents / metabolism
  • Phosphoric Monoester Hydrolases / metabolism*
  • Sequence Homology, Amino Acid
  • Substrate Specificity
  • Synaptic Transmission / physiology*
  • Synaptic Vesicles / metabolism


  • Inositol Phosphates
  • Neurotransmitter Agents
  • inositol 1,4-bis(phosphate)
  • inositol 1,3,4-trisphosphate
  • Lithium
  • Phosphoric Monoester Hydrolases
  • inositol-1,4-bisphosphate 1-phosphatase

Associated data

  • GENBANK/AF069513