Synapse - Synaptic Polarization

Synaptic Polarization

The function of neurons depends upon cellular polarization. The distinctive structure of nerve cells allows action potentials to travel directionally (from dendrites to axons), and for these signals to then be received and carried on by post-synaptic neurons or received by effector cells. Nerve cells have long been used as models for cellular polarization, and of particular interest are the mechanisms underlying the polarized localization of synaptic molecules. PIP2 signalling regulated by IMPase plays an integral role in synaptic polarity.

Phosphoinositides (PIP, PIP2, and PIP3) are molecules that have been shown to affect neuronal polarity. They are synthesized by combinational phosphorylation of phosphatidylinositol (PI), a phospholipid cell membrane component. PI is derived from myo-inositol, which is obtained via three pathways: uptake from the extracellular environment, synthesis from glucose, and the recycling of phosphoinositides. Both the synthesis of myo-inositol from glucose and the recycling of phosphoinositides require myo-inositol monophosphatase – IMPase – an enzyme that produces inositol by dephosphorylating inositol phosphate. IMPase has been studied in vivo at some length due to its relevance in the study of bipolar disorder resulting from its sensitivity to lithium. In 2006, a gene (ttx-7) was identified in Caenorhabditis elegans that encodes IMPase. Organisms with mutant ttx-7 genes demonstrated behavioral and localization defects, which were rescued by expression of IMPase and application of inositol. Wild type organisms treated with lithium displayed similar defects to those exhibited by the ttx-7 mutants. This led to the conclusion that IMPase is required for the correct localization of synaptic protein components.

The egl-8 gene encodes a homolog of phospholipase Cβ (PLCβ), an enzyme that cleaves PIP2. When ttx-7 mutants also had a mutant egl-8 gene, the defects caused by the faulty ttx-7 gene were largely reversed; this suggests that an accumulation of PIP2 corrected the adverse effects of the mutant ttx-7 gene. Furthermore, a mutation in the unc-26 gene (encoding a protein that dephosphorylates PIP2) suppressed the synaptic defects in the ttx-7 mutants. The egl-8 mutants were resistant to lithium treatment. This is genetic evidence that disruption of IMPase alters the levels of PIP2 in neurons; these results suggest that PIP2 signaling establishes polarized localization of synaptic components in living neurons.