Pelkey Kenneth A, Topolnik Lisa, Yuan Xiao-Qing, Lacaille Jean-Claude, McBain Chris J
Laboratory of Cellular and Synaptic Neurophysiology, National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA.
Neuron. 2008 Dec 26;60(6):980-7. doi: 10.1016/j.neuron.2008.11.018.
At hippocampal mossy fiber (MF)-st. lucidum interneuron (SLIN) synapses, mGluR7 serves as a metaplastic switch controlling bidirectional plasticity. mGluR7 activation during high-frequency stimulation (HFS) triggers presynaptic LTD due to persistent P/Q-type Ca(2+) channel inhibition. However, following mGluR7 internalization HFS produces presynaptic LTP. Surprisingly, LTP is not a simple molecular reversal of Ca(2+) channel depression. Rather, mGluR7 activation/internalization controls plasticity polarity by gating cAMP sensitivity of release. While naive surface mGluR7 expressing MF-SLIN synapses are insensitive to cAMP elevation, synapses that have internalized mGluR7 robustly potentiate following cAMP increases. Moreover, MF-SLIN LTP requires adenylate cyclase (AC) and protein kinase A (PKA) activities. We also discovered an association between mGluR7 and RIM1alpha, an active zone molecule required for AC/PKA-dependent presynaptic LTP. Importantly, the mGluR7-RIM1alpha interaction is regulated by mGluR7 activation, and mice lacking RIM1alpha are deficient in MF-SLIN LTP. We conclude that state-dependent cAMP sensitivity controlled by mGluR7-RIM1alpha interactions underlies MF-SLIN metaplasticity.
在海马苔藓纤维（MF）-透明层中间神经元（SLIN）突触中，代谢型谷氨酸受体7（mGluR7）作为一个控制双向可塑性的元可塑性开关。高频刺激（HFS）期间mGluR7的激活会由于持续性P/Q型钙通道抑制而触发突触前长时程抑制（LTD）。然而，在mGluR7内化后，HFS会产生突触前长时程增强（LTP）。令人惊讶的是，LTP并非钙通道抑制的简单分子逆转。相反，mGluR7的激活/内化通过控制释放对环磷酸腺苷（cAMP）的敏感性来控制可塑性极性。虽然表达mGluR7的幼稚表面MF-SLIN突触对cAMP升高不敏感，但已内化mGluR7的突触在cAMP增加后会强烈增强。此外，MF-SLIN LTP需要腺苷酸环化酶（AC）和蛋白激酶A（PKA）的活性。我们还发现了mGluR7与RIM1α之间的关联，RIM1α是AC/PKA依赖性突触前LTP所需的活性区分子。重要的是，mGluR7-RIM1α相互作用受mGluR7激活调节，缺乏RIM1α的小鼠在MF-SLIN LTP方面存在缺陷。我们得出结论，由mGluR7-RIM1α相互作用控制的状态依赖性cAMP敏感性是MF-SLIN元可塑性的基础。
