Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110.
Taylor Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO 63110.
eNeuro. 2017 Aug 21;4(4). doi: 10.1523/ENEURO.0176-17.2017. eCollection 2017 Jul-Aug.
Prior studies have found that dopamine (DA), acting at D4 receptors, and neuregulin (NRG), likely acting at ErbB4 receptors, are involved in a form of depotentiation of long-term potentiation (LTP) at Schaffer collateral (SC) synapses in the hippocampus. Furthermore, DA and NRG actions are intertwined in that NRG induces DA release. We previously found that low-frequency stimulation (LFS) of temperoammonic (TA) inputs to area CA1 also depotentiates previously established SC LTP through a complex signaling pathway involving endocannabinoids, GABA, adenosine, and mitogen-activated protein kinases (MAPKs), but not glutamate. In the present studies, we found that TA-induced SC depotentiation in hippocampal slices from Sprague-Dawley albino rats also involves activation of both D4 receptors and NRG-activated ErbB receptors, but that the roles of these two modulator systems are independent with D4 receptor antagonism failing to alter chemical depotentiation by NRG1β. Furthermore, a selective D4 receptor agonist was unable to depotentiate SC LTP when administered alone, suggesting that D4 receptor activation is necessary but not sufficient for TA-induced SC depotentiation. Chemical depotentiation by NRG1β was inhibited by a Pan-ErbB antagonist and by picrotoxin (PTX), an antagonist of GABA-A receptors (GABARs), indicating that NRG likely promotes SC depotentiation via effects on GABA and interneurons. These findings have implications for understanding the role of DA and NRG in cognitive dysfunction associated with neuropsychiatric illnesses.
先前的研究发现，多巴胺（DA）作用于 D4 受体，神经调节蛋白（NRG）可能作用于 ErbB4 受体，参与了海马体 Schaffer 侧支（SC）突触长时程增强（LTP）的一种去极化形式。此外，DA 和 NRG 的作用相互交织，NRG 诱导 DA 释放。我们之前发现，对 CA1 区的颞极铵（TA）输入进行低频刺激（LFS）也通过涉及内源性大麻素、GABA、腺苷和丝裂原活化蛋白激酶（MAPKs）的复杂信号通路，使先前建立的 SC LTP 去极化，但不涉及谷氨酸。在本研究中，我们发现 Sprague-Dawley 白化大鼠海马切片中 TA 诱导的 SC 去极化也涉及 D4 受体和 NRG 激活的 ErbB 受体的激活，但这两个调制系统的作用是独立的，D4 受体拮抗剂不能改变 NRG1β 的化学去极化。此外，单独给予选择性 D4 受体激动剂时不能使 SC LTP 去极化，表明 D4 受体的激活是必要的，但不足以引起 TA 诱导的 SC 去极化。NRG1β 的化学去极化被泛 ErbB 拮抗剂和 GABAA 受体（GABARs）拮抗剂 picrotocin（PTX）抑制，表明 NRG 可能通过对 GABA 和中间神经元的影响促进 SC 去极化。这些发现对于理解 DA 和 NRG 在与神经精神疾病相关的认知功能障碍中的作用具有重要意义。
