Choi Diane, Paré Jean-Francois, Dravid Shashank, Smith Yoland
Graduate Program in Molecular and Systems Pharmacology, Emory University, Atlanta, Georgia, USA.
Emory National Primate Research Center, Emory University, Atlanta, Georgia, USA.
J Comp Neurol. 2025 Jan;533(1):e70019. doi: 10.1002/cne.70019.
Glutamate delta receptor 1 (GluD1) is a unique synaptogenic molecule expressed at excitatory and inhibitory synapses. The lateral habenula (LHb), a subcortical structure that regulates negative reward prediction error and major monoaminergic systems, is enriched in GluD1. LHb dysfunction has been implicated in psychiatric disorders such as depression and schizophrenia, both of which are associated with GRID1, the gene that encodes GluD1. Thus, disruption in GluD1 synaptic signaling may contribute to LHb dysfunction and the pathophysiology of LHb-associated disorders. Despite its strong cellular expression, little is known about the subsynaptic and subcellular localization of GluD1 in LHb neurons. Given that GluD1 is involved in the development and/or regulation of glutamatergic and GABAergic synapses in various brain regions, a detailed map of GluD1 synaptic localization is essential to elucidate its role in the LHb. To address this issue, we used immunoelectron microscopy methods in rodents and monkeys. In both species, GluD1 immunoreactivity was primarily expressed in dendritic profiles, with lower expression in somata, spines, and glial elements. Pre- and post-embedding immunogold experiments revealed strong GluD1 expression in the core of symmetric GABAergic synapses. Albeit less frequent, GluD1 was also found at the edges (i.e., perisynaptic) of asymmetric, putative glutamatergic synapses. Through the combination of anterograde tracing with immunogold labeling in rats, we showed that axon terminals from the entopeduncular nucleus and the lateral hypothalamus express postsynaptic GluD1 immunolabeling in the LHb. Our findings suggest that GluD1 may play a critical role in modulating GABAergic transmission in the rodent and primate LHb.
谷氨酸δ受体1（GluD1）是一种独特的促突触分子，在兴奋性和抑制性突触中表达。外侧缰核（LHb）是一种调节负性奖励预测误差和主要单胺能系统的皮质下结构，富含GluD1。LHb功能障碍与抑郁症和精神分裂症等精神疾病有关，这两种疾病都与编码GluD1的基因GRID1相关。因此，GluD1突触信号的破坏可能导致LHb功能障碍以及与LHb相关疾病的病理生理学。尽管GluD1在细胞中表达强烈，但对其在LHb神经元中的突触下和亚细胞定位知之甚少。鉴于GluD1参与了不同脑区谷氨酸能和γ-氨基丁酸能（GABA能）突触的发育和/或调节，详细的GluD1突触定位图谱对于阐明其在LHb中的作用至关重要。为了解决这个问题，我们在啮齿动物和猴子中使用了免疫电子显微镜方法。在这两个物种中，GluD1免疫反应性主要在树突轮廓中表达，在胞体、棘突和神经胶质成分中的表达较低。包埋前和包埋后免疫金实验显示，在对称GABA能突触的核心有强烈的GluD1表达。虽然频率较低，但在不对称的、假定的谷氨酸能突触的边缘（即突触周围）也发现了GluD1。通过在大鼠中结合顺行追踪与免疫金标记，我们表明内苍白球核和外侧下丘脑的轴突终末在LHb中表达突触后GluD1免疫标记。我们的研究结果表明，GluD1可能在调节啮齿动物和灵长类动物LHb中的GABA能传递中起关键作用。
