Mutation and activation of Galpha s similarly alters pre- and postsynaptic mechanisms modulating neurotransmission

J Neurophysiol. 2003 May;89(5):2620-38. doi: 10.1152/jn.01072.2002. Epub 2003 Jan 22.

Abstract

Constitutive activation of Galphas in the Drosophila brain abolishes associative learning, a behavioral disruption far worse than that observed in any single cAMP metabolic mutant, suggesting that Galphas is essential for synaptic plasticity. The intent of this study was to examine the role of Galphas in regulating synaptic function by targeting constitutively active Galphas to either pre- or postsynaptic cells and by examining loss-of-function Galphas mutants (dgs) at the glutamatergic neuromuscular junction (NMJ) model synapse. Surprisingly, both loss of Galphas and activation of Galphas in either pre- or postsynaptic compartment similarly increased basal neurotransmission, decreased short-term plasticity (facilitation and augmentation), and abolished posttetanic potentiation. Elevated synaptic function was specific to an evoked neurotransmission pathway because both spontaneous synaptic vesicle fusion frequency and amplitude were unaltered in all mutants. In the postsynaptic cell, the glutamate receptor field was regulated by Galphas activity; based on immunocytochemical studies, GluRIIA receptor subunits were dramatically downregulated (>75% decrease) in both loss and constitutive active Galphas genotypes. In the presynaptic cell, the synaptic vesicle cycle was regulated by Galphas activity; based on FM1-43 dye imaging studies, evoked vesicle fusion rate was increased in both loss and constitutively active Galphas genotypes. An important conclusion of this study is that both increased and decreased Galphas activity very similarly alters pre- and postsynaptic mechanisms. A second important conclusion is that Galphas activity induces transynaptic signaling; targeted Galphas activation in the presynapse downregulates postsynaptic GluRIIA receptors, whereas targeted Galphas activation in the postsynapse enhances presynaptic vesicle cycling.

Publication types

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

MeSH terms

  • Animals
  • Cyclic AMP / physiology
  • Down-Regulation / physiology
  • Drosophila
  • Electric Stimulation
  • Electrophysiology
  • GTP-Binding Protein alpha Subunits, Gs / genetics*
  • GTP-Binding Protein alpha Subunits, Gs / physiology*
  • Immunohistochemistry
  • Larva
  • Microscopy, Confocal
  • Mutation / genetics
  • Mutation / physiology*
  • Neuronal Plasticity / genetics
  • Neuronal Plasticity / physiology
  • Patch-Clamp Techniques
  • Receptors, Glutamate / physiology
  • Receptors, Presynaptic / genetics*
  • Receptors, Presynaptic / physiology*
  • Synapses / physiology*
  • Synaptic Transmission / genetics*
  • Synaptic Transmission / physiology*

Substances

  • Receptors, Glutamate
  • Receptors, Presynaptic
  • Cyclic AMP
  • GTP-Binding Protein alpha Subunits, Gs