Shim Hyun Geun, Jang Sung-Soo, Jang Dong Cheol, Jin Yunju, Chang Wonseok, Park Joo Min, Kim Sang Jeong
Department of Physiology, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Biomedical Science, Seoul National University College of Medicine, Seoul, Republic of Korea;
Department of Physiology, Seoul National University College of Medicine, Seoul, Republic of Korea; Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea;
J Neurophysiol. 2016 Jun 1;115(5):2446-55. doi: 10.1152/jn.00566.2015. Epub 2016 Feb 24.
Homeostatic intrinsic plasticity is a cellular mechanism for maintaining a stable neuronal activity level in response to developmental or activity-dependent changes. Type 1 metabotropic glutamate receptor (mGlu1 receptor) has been widely known to monitor neuronal activity, which plays a role as a modulator of intrinsic and synaptic plasticity of neurons. Whether mGlu1 receptor contributes to the compensatory adjustment of Purkinje cells (PCs), the sole output of the cerebellar cortex, in response to chronic changes in excitability remains unclear. Here, we demonstrate that the mGlu1 receptor is involved in homeostatic intrinsic plasticity through the upregulation of the hyperpolarization-activated current (Ih) in cerebellar PCs. This plasticity was prevented by inhibiting the mGlu1 receptor with Bay 36-7620, an mGlu1 receptor inverse agonist, but not with CPCCOEt, a neutral antagonist. Chronic inactivation with tetrodotoxin (TTX) increased the components of Ih in the PCs, and ZD 7288, a hyperpolarization-activated cyclic nucleotide-gated channel selective inhibitor, fully restored reduction of firing rates in the deprived neurons. The homeostatic elevation of Ih was also prevented by BAY 36-7620, but not CPCCOEt. Furthermore, KT 5720, a blocker of protein kinase A (PKA), prevented the effect of TTX reducing the evoked firing rates, indicating the reduction in excitability of PCs due to PKA activation. Our study shows that both the mGlu1 receptor and the PKA pathway are involved in the homeostatic intrinsic plasticity of PCs after chronic blockade of the network activity, which provides a novel understanding on how cerebellar PCs can preserve the homeostatic state under activity-deprived conditions.
稳态固有可塑性是一种细胞机制，用于响应发育或活动依赖性变化来维持稳定的神经元活动水平。1型代谢型谷氨酸受体（mGlu1受体）作为神经元活动的监测器广为人知，它在神经元的固有和突触可塑性调节中发挥作用。mGlu1受体是否有助于小脑皮质唯一的输出神经元——浦肯野细胞（PCs）对兴奋性慢性变化做出补偿性调整仍不清楚。在此，我们证明mGlu1受体通过上调小脑PCs中的超极化激活电流（Ih）参与稳态固有可塑性。用mGlu1受体反向激动剂Bay 36 - 7620抑制mGlu1受体可阻止这种可塑性，但用中性拮抗剂CPCCOEt则不能。用河豚毒素（TTX）进行慢性失活可增加PCs中Ih的成分，而超极化激活环核苷酸门控通道选择性抑制剂ZD 7288可完全恢复剥夺神经元中放电率的降低。Ih的稳态升高也被Bay 36 - 7620阻止，但未被CPCCOEt阻止。此外，蛋白激酶A（PKA）的阻滞剂KT 5720阻止了TTX降低诱发放电率的作用，表明PCs兴奋性降低是由于PKA激活所致。我们的研究表明，mGlu1受体和PKA途径都参与了网络活动慢性阻断后PCs的稳态固有可塑性，这为小脑PCs如何在活动剥夺条件下维持稳态提供了新的认识。
