Group III metabotropic glutamate receptors maintain tonic inhibition of excitatory synaptic input to hypocretin/orexin neurons
Group III metabotropic glutamate receptors maintain tonic inhibition of excitatory synaptic input to hypocretin/orexin neurons
复制标题
DOI：
10.1523/jneurosci.5416-03.2004
复制
发表时间：
2004-03-24
影响因子：
5.3
通讯作者：
van den Pol, AN
中科院分区：
文献类型：
--
作者：
Acuna-Goycolea, C;Li, Y;van den Pol, AN
下丘脑分泌素/食欲素神经元在下丘脑唤醒中发挥重要作用。下丘脑分泌素神经元的突触谷氨酸输入调节细胞放电。我们使用小鼠整个下丘脑切片或仅由外侧下丘脑组成的微切片的全细胞电压和电流钳记录，研究了 III 族代谢型谷氨酸受体 (mGluR) 在调节下丘脑分泌素神经元活性中的作用。使用选择性绿色荧光蛋白表达来检测活的下丘脑分泌素神经元。 mGluR 激动剂 L-(+)-2-氨基-4-磷酸丁酸 (L-AP-4) 以剂量依赖性方式抑制下丘脑分泌素神经元的突触输入；自发的谷氨酸和 GABA 介导的突触电流频率均降低。 L-AP-4 还降低了由放置在记录细胞内侧或外侧的刺激电极引起的突触后电位的幅度。未发现 L-AP-4 与膜电位、输入电阻或 AMPA 诱发电流相关的突触后效应。 L-AP-4 似乎通过突触前机制起作用，降低了河豚毒素存在下记录的谷氨酸和 GABA 介导的微型事件的频率，但幅度没有变化。 (RS)-膦基戊酸 (CPPG) 是一种 III 族 mGluR 拮抗剂，可抑制 L-AP-4 的作用。令人感兴趣的是，CPPG 本身增加了下丘脑分泌素神经元中记录的突触活动，表明持续的抑制音调可归因于 III 组 mGluR 的激活。谷氨酸能中间神经元被认为在下丘脑分泌素神经元上的下丘脑分泌素的正反馈募集中发挥作用。 L-AP-4 阻断下丘脑分泌素介导的 EPSC 增加，并减弱下丘脑分泌素介导的尖峰频率增加。总之，这些数据表明，紧张活性抑制性 mGluR 在外侧下丘脑内局部下丘脑分泌素敏感的谷氨酸神经元上表达，调节下丘脑分泌素唤醒系统的输出。
Hypocretin/orexin neurons play an important role in hypothalamic arousal. Synaptic glutamate input to hypocretin neurons regulates cell firing. We studied the actions of group III metabotropic glutamate receptors (mGluRs) in modulating the activity of hypocretin neurons using whole-cell voltage-and current-clamp recording in mouse whole hypothalamic slices or minislices consisting only of the lateral hypothalamus. Selective green fluorescent protein expression was used to detect live hypocretin neurons. The mGluR agonist L-(+)-2-amino-4-phosphonobutyric acid (L-AP-4) inhibited synaptic input to hypocretin neurons in a dose-dependent manner; both spontaneous glutamate and GABA-mediated synaptic currents were reduced in frequency. L-AP-4 also reduced the amplitude of postsynaptic potentials evoked by a stimulating electrode placed medial or lateral to the recorded cell. No postsynaptic effect of L-AP-4 was found relative to membrane potential, input resistance, or AMPA-evoked currents. L-AP-4 appeared to act by a presynaptic mechanism and reduced the frequency of both glutamate- and GABA-mediated miniature events recorded in the presence of tetrodotoxin, with no change in amplitude. (RS)-phosphonopentanoic acid (CPPG), a group III mGluR antagonist, suppressed the actions of L-AP-4. Of substantial interest, CPPG by itself increased synaptic activity recorded in hypocretin neurons, suggesting an ongoing inhibitory tone attributable to activation of group III mGluRs. Glutamatergic interneurons have been suggested to play a role in a positive feedback recruitment of hypocretin on hypocretin neurons. L-AP-4 blocked hypocretin-mediated increases in EPSCs and attenuated the hypocretin-mediated increase in spike frequency. Together, these data suggest that tonically active inhibitory mGluRs are expressed on local hypocretin-sensitive glutamate neurons within the lateral hypothalamus that modulate the output of the hypocretin arousal system.