PT  - JOURNAL ARTICLE
AU  - Crawford, Devon C.
AU  - Chang, Chun Yun
AU  - Hyrc, Krzysztof L.
AU  - Mennerick, Steven
TI  - Calcium-Independent Inhibitory G-Protein Signaling Induces Persistent Presynaptic Muting of Hippocampal Synapses
AID  - 10.1523/JNEUROSCI.4960-10.2011
DP  - 2011 Jan 19
TA  - The Journal of Neuroscience
PG  - 979--991
VI  - 31
IP  - 3
4099  - http://www.jneurosci.org/content/31/3/979.short
4100  - http://www.jneurosci.org/content/31/3/979.full
SO  - J. Neurosci.2011 Jan 19; 31
AB  - Adaptive forms of synaptic plasticity that reduce excitatory synaptic transmission in response to prolonged increases in neuronal activity may prevent runaway positive feedback in neuronal circuits. In hippocampal neurons, for example, glutamatergic presynaptic terminals are selectively silenced, creating “mute” synapses, after periods of increased neuronal activity or sustained depolarization. Previous work suggests that cAMP-dependent and proteasome-dependent mechanisms participate in silencing induction by depolarization, but upstream activators are unknown. We, therefore, tested the role of calcium and G-protein signaling in silencing induction in cultured hippocampal neurons. We found that silencing induction by depolarization was not dependent on rises in intracellular calcium, from either extracellular or intracellular sources. Silencing was, however, pertussis toxin sensitive, which suggests that inhibitory G-proteins are recruited. Surprisingly, blocking four common inhibitory G-protein-coupled receptors (GPCRs) (adenosine A1 receptors, GABAB receptors, metabotropic glutamate receptors, and CB1 cannabinoid receptors) and one ionotropic receptor with metabotropic properties (kainate receptors) failed to prevent depolarization-induced silencing. Activating a subset of these GPCRs (A1 and GABAB) with agonist application induced silencing, however, which supports the hypothesis that G-protein activation is a critical step in silencing. Overall, our results suggest that depolarization activates silencing through an atypical GPCR or through receptor-independent G-protein activation. GPCR agonist-induced silencing exhibited dependence on the ubiquitin-proteasome system, as was shown previously for depolarization-induced silencing, implicating the degradation of vital synaptic proteins in silencing by GPCR activation. These data suggest that presynaptic muting in hippocampal neurons uses a G-protein-dependent but calcium-independent mechanism to depress presynaptic vesicle release.