Metabotropic glutamate receptor gates LTP induction in hippocampus

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Long-term potentiation(LTP) of synaptic transmission has been regarded as the neuronal basis underlying memory formation. In the CA1 region of the hippocampus, LTP induction has been supposed to require the coincident activation of pre-and postsynaptic neurons, as described in Hebbian hypothesis. Since the Ca^<2+> influx through N-methyl-D-aspartate receptors(NMDARs) plays a crucial role in the induction of LTP, NMDARs, with their characteristics as a coincident detector, are widely accepted as the molecular basis of Hebbian LTP. In contrast, the role of Ca^<2+> influx through voltage-dependent calcium channels(VDCCs) has not been fully addressed yet. Here, we found that LTP can be induced by postsynaptic repetitive depolarization alone in the absence of presynaptic inputs, which was dependent on VDCCs instead of NMDARs, and this form of LTP was non-Hebbian neuron-wide nature.Also, while the metabotropic glutamate receptor(mGluR) is supposed to modulate VDCCs, its role in LTP has not been well characterized yet. By using subtype-specific knockout mice, we found that mGluR5 induces facilitation of the depolarization-evoked calcium current, which is dependent on the activation of calcium-induced calcium release(CICR) triggered by VDCC. We also showed that mGluR5 enhanced VDCC-dependent LTP of synaptic transmission. We found that L-type VDCCs andmGluR5 form a complex by coimmunoprecipitation, suggesting that the specific functional coupling between mGluR5, InsP_3 receptors(InsP_3Rs) and L-VDCCs played a pivotal role in the calcium-current facilitation.Taken together, the present study has identified a novel mechanism of the interaction between the mGluR and calcium signaling, and suggested contribution of mGluR5 to neuron-wide non-Hebbian plasticity which works in concert with synapse-specific Hebbian plasticity to help information processing in memory formation.