GluD1, linked to schizophrenia, controls the burst firing of dopamine neurons.
GluD1, linked to schizophrenia, controls the burst firing of dopamine neurons.
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DOI：
10.1038/mp.2017.137
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发表时间：
2018-03
影响因子：
11
通讯作者：
Tricoire L
中科院分区：
文献类型：
--
作者：
Benamer N;Marti F;Lujan R;Hepp R;Aubier TG;Dupin AAM;Frébourg G;Pons S;Maskos U;Faure P;Hay YA;Lambolez B;Tricoire L
编码孤儿 delta1 谷氨酸受体通道 (GluD1) 的 GRID1 基因的人类突变与精神分裂症有关，但 GluD1 在脑回路中的明确作用尚不清楚。基于其旁系同源物 GluD2 在小脑中的已知功能，我们寻找 GluD1 在中脑多巴胺神经元中代谢型受体 mGlu1 介导的缓慢谷氨酸能传递中的作用，中脑多巴胺神经元的功能障碍是精神分裂症的标志。我们发现 mGlu1 激动剂在共表达 mGlu1 和 GluD1 的 HEK 细胞中引起缓慢的去极化电流，但在单独表达 mGlu1 或 GluD1 的细胞中则不会。该电流被显性失活 GluD1 死孔突变体的额外共表达所消除。然后，我们从中脑切片中表征了多巴胺神经元中 mGlu1 依赖性电流。显性失活 GluD1 突变体的表达消除了激动剂诱发的电流和缓慢的突触后电流，表明天然 GluD1 通道参与了这些电流。同样，两种 mGlu1 依赖性电流在 GRID1 敲除小鼠中均受到抑制，据报道这些小鼠表现出与精神分裂症相关的内表型。众所周知，mGlu1 激活会触发多巴胺神经元从强直性向爆发性放电的转变，从而发出显着刺激信号并编码奖励预测。多巴胺神经元的体内记录表明，GRID1 敲除小鼠中或野生型小鼠中显性失活 GluD1 突变体的靶向表达后，它们的自发爆发被消除。我们的研究结果消除了 GluD1 的孤儿效应，揭示了其在缓慢谷氨酸传递中的关键作用，并为 GRID1 基因改变如何导致精神分裂症中的多巴胺能功能障碍提供了见解。
Human mutations of the GRID1 gene encoding the orphan delta1 glutamate receptor-channel (GluD1) are associated with schizophrenia but the explicit role of GluD1 in brain circuits is unknown. Based on the known function of its paralog GluD2 in cerebellum, we searched for a role of GluD1 in slow glutamatergic transmission mediated by metabotropic receptor mGlu1 in midbrain dopamine neurons, whose dysfunction is a hallmark of schizophrenia. We found that an mGlu1 agonist elicits a slow depolarizing current in HEK cells co-expressing mGlu1 and GluD1, but not in cells expressing mGlu1 or GluD1 alone. This current is abolished by additional co-expression of a dominant-negative GluD1 dead pore mutant. We then characterized mGlu1-dependent currents in dopamine neurons from midbrain slices. Both the agonist-evoked and the slow postsynaptic currents are abolished by expression of the dominant-negative GluD1 mutant, pointing to the involvement of native GluD1 channels in these currents. Likewise, both mGlu1-dependent currents are suppressed in GRID1 knockout mice, which reportedly display endophenotypes relevant for schizophrenia. It is known that mGlu1 activation triggers the transition from tonic to burst firing of dopamine neurons, which signals salient stimuli and encodes reward prediction. In vivo recordings of dopamine neurons showed that their spontaneous burst firing is abolished in GRID1 knockout mice or upon targeted expression of the dominant-negative GluD1 mutant in wild-type mice. Our results de-orphanize GluD1, unravel its key role in slow glutamatergic transmission and provide insights into how GRID1 gene alterations can lead to dopaminergic dysfunctions in schizophrenia.
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