Bidirectional modulation of glutamatergic synaptic transmission by metabotropic glutamate type 7 receptors at Schaffer collateral–CA1 hippocampal synapses

Abstract

Neurotransmitter release is driven by Ca influx at synaptic boutons that acts on synaptic vesicles ready to undergo exocytosis. Neurotransmitter release is inhibited when metabotropic glutamate type 7 (mGlu ) receptors provoke a reduction in Ca influx, although the reduced release from synapses lacking this receptor suggests that they may also prime synaptic vesicles for release. These mGlu receptors activate phospholipase C (PLC) and generate inositol trisphosphate, which in turn releases Ca from intracellular stores and produces diacylglycerol (DAG), an activator of proteins containing DAG-binding domains such as Munc13 and protein kinase C (PKC). However, the full effects of mGlu receptor signalling on synaptic transmission are unclear. We found that prolonged activation of mGlu receptors with the agonist l-AP4 first reduces and then enhances the amplitude of EPSCs, a presynaptic effect that changes the frequency but not the amplitude of the mEPSCs and the paired pulse ratio. Pertussis toxin blocks the inhibitory response, while the PLC inhibitor U73122, and the inhibitor of DAG binding calphostin C, prevent receptor mediated potentiation. Moreover, this DAG-dependent potentiation of the release machinery brings more synaptic vesicles closer to the active zone plasma membrane in a Munc13-2- and RIM1α-dependent manner. Electrically evoked release of glutamate that activates mGlu receptors also bidirectionally modulates synaptic transmission. In these conditions, potentiation now occurs rapidly and it overcomes any inhibition, such that potentiation prevails unless it is suppressed with the PLC inhibitor U73122.

β-Adrenergic Receptors/Epac Signaling Increases the Size of the Readily Releasable Pool of Synaptic Vesicles Required for Parallel Fiber LTP

“…The priming activity of Munc13 (Ma et al, 2011) plays a key role in SV docking through assembly of the Munc13-Rim1-Rab3 complex (Dulubova et al, 2005) and SNARE complex. Munc13-1 forms supramolecular self-assemblies that serve as independent release sites (Sakamoto et al, 2018) through which phospholipase C (PLC)-coupled receptors (Bauer et al, 2007;Martín et al, 2010) enhance the RRP size (Martín et al, 2018). b ARs and Epac also activate PLC, translocate Munc13-1, enhance Rab3A-RIM1a interaction, and increase SV docking (Ferrero et al, 2013).…”

Metabotropic Glutamate Receptor 7: A New Therapeutic Target in Neurodevelopmental Disorders

“…While further studies will be needed to explain the current discrepancy between genetic and pharmacological approaches, these data indicate that mGlu 7 regulates high-frequency transmission at SC-CA1 synapses. Recently, Martín et al (2018) demonstrated that prolonged activation of mGlu 7 leads to potentiation of excitatory post-synaptic currents recorded by pyramidal cells in CA1. This potentiation of neurotransmitter release is dependent on PLC and the vesicle release proteins Munc13-2 and Rim1α.…”

Neddylation is required for presynaptic clustering of mGlu7 and maturation of presynaptic terminals

“…mGlu7 has been shown to inhibit neurotransmitter release upon the activation of G i/o and the subsequent inhibition of calcium channels 33 , 34 . However, recent evidence has suggested that the prolonged activation of mGlu7 facilitates glutamate release via a G i/o -independent pathway through the translocation of Munc13 to the particulate fraction 35 , 36 . The deneddylated mGlu7 mislocalized from the active zone may no longer regulate synaptic vesicle release, thereby reducing the release probability.…”