Bidirectional modulation of glutamatergic synaptic transmission by mGlu7 receptors at SC-CA1 hippocampal synapses

Abstract

Neurotransmitter release is driven by Ca²⁺ influx at synaptic boutons that acts on synaptic vesicles ready to undergo exocytosis. Neurotransmitter release is inhibited when mGlu₇ receptors provoke a reduction in Ca²⁺ influx, although the reduced release from synapses lacking this receptor suggests that they may also prime synaptic vesicles for release. These mGlu₇ receptors activate phospholipase C (PLC) and generate inositol trisphosphate (IP₃), which in turn releases Ca²⁺ from intracellular stores and produces diacylglycerol (DAG), an activator of proteins containing DAG-binding domains like Munc13 and protein kinase C (PKC). However, the full effects of mGlu₇ receptor signalling on synaptic transmission are unclear. We found that prolonged activation of mGlu₇ 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 mGlu₇ receptors also bi-directionally 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.

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