J Neurophysiol (May 1, 2003). 10.1152/jn.01072.2002
Submitted on Submitted 27 November 2002; accepted in final form 17 January 2003

Mutation and Activation of Gs Similarly Alters Pre- and Postsynaptic Mechanisms Modulating Neurotransmission

 ¹Interdepartmental Program in Neuroscience, University of Utah, Salt Lake City, Utah 84112-0840; and  ²Center for Molecular Neuroscience, Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee 37235-1634

Renden, Robert B. and Kendal Broadie. Mutation and Activation of Gs Similarly Alters Pre- and Postsynaptic Mechanisms Modulating Neurotransmission. J. Neurophysiol. 89: 2620-2638, 2003. Constitutive activation of Gs in the Drosophila brain abolishes associative learning, a behavioral disruption far worse than that observed in any single cAMP metabolic mutant, suggesting that Gs is essential for synaptic plasticity. The intent of this study was to examine the role of Gs in regulating synaptic function by targeting constitutively active Gs to either pre- or postsynaptic cells and by examining loss-of-function Gs mutants (dgs) at the glutamatergic neuromuscular junction (NMJ) model synapse. Surprisingly, both loss of Gs and activation of Gs 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 Gs activity; based on immunocytochemical studies, GluRIIA receptor subunits were dramatically downregulated (>75% decrease) in both loss and constitutive active Gs genotypes. In the presynaptic cell, the synaptic vesicle cycle was regulated by Gs activity; based on FM1-43 dye imaging studies, evoked vesicle fusion rate was increased in both loss and constitutively active Gs genotypes. An important conclusion of this study is that both increased and decreased Gs activity very similarly alters pre- and postsynaptic mechanisms. A second important conclusion is that Gs activity induces transynaptic signaling; targeted Gs activation in the presynapse downregulates postsynaptic GluRIIA receptors, whereas targeted Gs activation in the postsynapse enhances presynaptic vesicle cycling.