Metabotropic glutamate receptor gates LTP induction in hippocampus

突触传递的长时程增强(LTP)被认为是记忆形成的神经元基础。在海马区的CA1区，LTP的诱导被认为需要突触前和突触后神经元的一致激活，如Hebbian假说所描述的那样。由于通过N-甲基-D-天冬氨酸受体(NMDARs)的钙离子内流在LTP的诱导过程中起着关键作用，NMDARs作为符合检测器的特性被广泛认为是Hebbian LTP的分子基础。相反，钙离子通过电压依赖性钙通道(VDCC)内流的作用尚未完全阐明。在这里，我们发现在没有突触前输入的情况下，LTP可以由突触后重复去极化单独诱导，这依赖于VDCCs而不是NMDAR，并且这种形式的LTP是非Hebbian神经元范围的性质。此外，尽管代谢性谷氨酸受体(MGluR)被认为调制VDCC，但其在LTP中的作用尚未得到很好的研究。通过使用亚型特异性基因敲除小鼠，我们发现mGluR5诱导去极化诱发的钙电流的易化，这依赖于VDCC触发的钙诱导钙释放(CICR)的激活。我们还发现mGluR5增强了VDCC依赖的突触传递的LTP。我们发现L类VDCC与mGluR5通过免疫共沉淀形成复合体，提示mGluR5、InSP3受体(InSP3Rs)和L VDCCs之间的特异性功能偶联在钙电流易化中起着关键作用。综上所述，本研究发现了mGluR与钙信号相互作用的新机制，并提出mGluR5对神经元范围的非Hebbian可塑性的贡献与突触特异性Hebbian可塑性协同作用，以帮助记忆形成中的信息处理。

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.