Role of presynaptic metabotropic glutamate receptors in the induction of long-term synaptic plasticity of vesicular release

Abstract

While postsynaptic ionotropic and metabotropic glutamate receptors have received the lions share of attention in studies of long-term activity-dependent synaptic plasticity, it is becoming clear that presynaptic metabotropic glutamate receptors play critical roles in both short-term and long-term plasticity of vesicular transmitter release, and that they act both at the level of voltage-dependent calcium channels and directly on proteins of the vesicular release machinery. Activation of G protein-coupled receptors can transiently inhibit vesicular release through the release of Gβγ which binds to both voltage-dependent calcium channels to reduce calcium influx, and directly to the C-terminus region of the SNARE protein SNAP-25. Our recent work has revealed that the binding of Gβγ to SNAP-25 is necessary, but not sufficient, to elicit long-term depression (LTD) of vesicular glutamate release, and that the concomitant release of Gαi and the second messenger nitric oxide are also necessary steps in the presynaptic LTD cascade. Here, we review the current state of knowledge of the molecular steps mediating short-term and long-term plasticity of vesicular release at glutamatergic synapses, and the many gaps that remain to be addressed.

Presynaptic long-term depression mediated by Gi/o-coupled receptors

“…Nitric oxide (NO) signaling can intersect with GPCR-mediated LTD through NO-signaling pathway-mediated Ca 2+ release from presynaptic internal stores and subsequent activation of Ca 2+ -sensitive LTD mediators. Protein kinase G (PKG)-mediatedphosphorylation of release machinery may also contribute to these forms of LTD [40–42]. While these mechanisms can be recruited for presynaptic LTD induction, the maintenance of this form of LTD requires long-lasting changes at axon terminals possibly accomplished by alterations in protein translation or posttranslational modification.…”

The antiepileptogenic effect of low-frequency stimulation on perforant path kindling involves changes in regulators of G-protein signaling in rat

“…These results are not inconsistent with the previous reports that showed an increase in the expression of α subunit of G o protein in dentate gyrus of amygdala kindled rats (Lason and Przewlocki, 1994) and a decrease in immunoreactivity levels of α subunit of G i/o protein in amygdala, piriform cortex and hippocampus at 24 h post seizure (Cutz et al, 1996). On the other hand, pharmacological studies have shown that G i/o protein-coupled receptors (such as metabotropic glutamatergic receptors) are involved in the inhibitory effects of LFS on synaptic strength (Upreti et al;Xu et al, 2010;Atwood et al, 2014). Our previous studies also showed the involvement of adenosine A 1 and galanin (GALR1 and GALR2) receptors in mediating the antiepileptogenic effects of LFS in kindling (Sadegh et al, 2007;Mohammad-Zadeh et al, 2009).…”

Synaptic plasticity mechanisms common to learning and alcohol use disorder

“…Different forms of LTD have been described at glutamatergic synapses, involving both pre-and postsynaptic mechanisms (Collingridge et al 2010). The predominant mechanism underlying presynaptic LTD is decreased probability of neurotransmitter release (Upreti et al 2013;Atwood et al 2014b). Activation of a variety of G protein-coupled receptors (GPCRs) that signal through G i/o -type G proteins can induce LTD at synapses throughout the brain (Atwood et al 2014b).…”

“…In many cases, this synaptic depression outlasts CB1 activation, and this is defined at eCB-LTD (Castillo et al 2012;Augustin and Lovinger 2018). Other signaling mechanisms have also been reported to produce presynaptic LTD (e.g., nitric oxide) (Upreti et al 2013). The intra-terminal signaling mechanisms involved in G i/o -induced presynaptic LTD expression appear to include decreased cAMP production and PKA activation, as well as protein translation involving presynaptic RNA Castillo et al 2012;Younts et al 2016).…”