MGLUR7 MODULATION OF PARVALBUMIN-CA1 SYNAPSES CONTROLS SPATIAL MEMORY AND ANTI-EPILEPTIC ACTIVITY

mGluR7 is a presynaptic metabotropic glutamate receptor enriched at the active zone, where it modulates neurotransmitter release. Brief activation of mGluR7 activates G_i/o proteins and reduces neurotransmitter release by blocking voltage-gated Ca²⁺ channels. However, prolonged activation of mGluR7 at Schaffer collateral–CA1 (SC–CA1) synapses enhances excitatory transmission through a non-canonical signaling cascade involving phospholipase C activation by a pertussis toxin–resistant G-protein and diacylglycerol-mediated activation of synaptic vesicle docking by Munc13-2. Since mGluR7 is also expressed at presynaptic terminals of parvalbumin expressing interneurons (PV), we investigated its ability to bidirectionally modulate synaptic transmission at PV-CA1 synapses.
Recording IPSCs from CA1 pyramidal cells induced by SC stimulation, we demonstrated that prolonged receptor activation causes an initial reduction followed by a potentiation of IPSC amplitude. The inhibitory phase is sensitive to pertussis toxin, whereas the potentiation phase is abolished by the DAG-binding inhibitor calphostin C. Potentiation was associated with an increase in miniature IPSC frequency, without changes in amplitude, as well as an increase of synaptic vesicle docking, measured by electron microscopy. Endogenous activation of mGluR7 by high-frequency stimulation also potentiated inhibitory transmission; this effect was blocked by group III mGluR antagonists, calphostin C, and was absent in slices from mGluR7 knockout mice. Finally, selective deletion of mGluR7 from PV–CA1 synapses abolished the aforementioned inhibitory plasticity, increased susceptibility to kainate-induced seizures, and impaired spatial memory, whereas deletion at SC–CA1 synapses had no effect. These findings identify mGluR7 as a key regulator of inhibitory synaptic plasticity and hippocampal network stability.