GABA neurotransmission in the hypothalamus: developmental reversal from Ca2+ elevating to depressing
GABA neurotransmission in the hypothalamus: developmental reversal from Ca2+ elevating to depressing
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下丘脑中的 GABA 神经传递：从 Ca2 升高到降低的发育逆转
DOI：
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发表时间：
1995
影响因子：
5.3
通讯作者：
A. N. V. D. Poised
中科院分区：
文献类型：
--
作者：
K. Obrietan;A. N. V. D. Poised
GABA 是成人下丘脑的主要抑制性递质，由许多神经元合成，存在于 50% 的突触前神经元中。 GABA 通过打开 Cl- 通道抑制细胞活性，导致体外成熟下丘脑神经元中 Ca2+ 的减少。尽管 GABAA 受体在胚胎下丘脑 (E15) 中早期表达，但 GABA 在发育中的下丘脑中的细胞功能很少受到关注。在本研究中，通过 fura-2 数字成像研究了 GABA 在调节下丘脑神经元发育中细胞内 Ca2+ 中的作用。将 GABA (0.5-500 µM) 应用于胚胎下丘脑神经元会引起细胞内 Ca2+ 急剧而快速的增加。这种 Ca2+ 的增加可以被 GABAA 拮抗剂荷包牡丹碱 (20 µM) 完全阻断，并在河豚毒素 (1 µM) 存在的情况下持续存在。在发育早期，GABA 诱导的 Ca2+ 升高大于等摩尔浓度的兴奋性递质谷氨酸。在培养的最初几天内，对 GABA 做出反应并导致 Ca2+ 升高的 E15 神经元数量增加，在体外培养 4 天后达到 78%。 Ca2+ 升高被镉 (100 µM) 阻断 87%，尼莫地平 (1 µM) 阻断 85%，表明 Ca2+ 升高的机制主要是通过 L 型电压操作的 Ca2+ 通道。在突触偶联培养物中添加荷包牡丹碱会导致培养后 4-10 天 Ca2+ 显着下降，表明下丘脑神经元在发育早期就分泌 GABA，并且释放了足够的 GABA 以引起 Ca2+ 增加。即使用谷氨酸受体拮抗剂阻断所有谷氨酸能活性后，仍能看到这种效果。相比之下，GABA 不会引起老年神经元中 Ca2+ 的升高（体外 > 18 天），而荷包牡丹碱的作用则相反，导致自发活动神经元中 Ca2+ 的大量增加。在富含来自视交叉上核的 GABA 能神经元的培养物中也获得了类似的结果。为了确定 GABA 对神经元发育的 Ca2+ 刺激作用是否仅限于下丘脑和其他一些区域，或者它是否可能存在于整个大脑，我们检查了培养的嗅球、皮质、髓质、纹状体、丘脑、海马和丘中的 Ca2+ 反应。每个区域的大多数（75%）发育中的神经元都表现出对 GABA 的反应而导致 Ca2+ 升高。这些数据共同表明，GABA 会升高下丘脑和所有其他检查大脑区域的发育中神经元的 Ca2+，但不会升高成熟神经元的 Ca2+ 水平。
GABA is the primary inhibitory transmitter of the adult hypothalamus, synthesized by many neurons and found in 50% of the presynaptic boutons. GABA causes a decrease in Ca2+ in mature hypothalamic neurons in vitro by depressing cellular activity through opening Cl- channels. Despite the early expression of GABAA receptors in the embryonic hypothalamus (E15), the cellular function of GABA in the developing hypothalamus has received little attention. In the present study the role of GABA in modulating intracellular Ca2+ in developing hypothalamic neurons was studied with fura-2 digital imaging. GABA (0.5- 500 microM) applied to embryonic hypothalamic neurons elicited a dramatic and rapid increase in intracellular Ca2+ This Ca2+ rise could be completely blocked by the GABAA antagonist bicuculline (20 microM) and persisted in the presence of tetrodotoxin (1 microM). The Ca2+ elevation induced by GABA was greater than that of equimolar concentrations of the excitatory transmitter glutamate in early development. The number of E15 neurons that responded to GABA with a Ca2+ rise increased during the first few days of culture, reaching 78% after 4 d in vitro. The Ca2+ rise was 87% blocked by cadmium (100 microM) and 85% blocked by nimodipine (1 microM), indicating that the mechanism of Ca2+ increase was primarily via L-type voltage operated Ca2+ channels. Addition of bicuculline to synaptically coupled cultures caused a significant decrease in Ca2+ 4–10 d after culturing, indicating hypothalamic neurons were secreting GABA at an early age of development, and that sufficient GABA was released to elicit an increase in Ca2+. This effect was seen even after blocking all glutamatergic activity with glutamate receptor antagonists. In contrast, GABA elicited no Ca2+ rise in older neurons (> 18 d in vitro), and the action of bicuculline reversed and caused a large increase in Ca2+ in spontaneously active neurons. Similar findings were obtained in cultures enriched in GABAergic neurons from the suprachiasmatic nucleus. To determine if the Ca2+ stimulating role of GABA on developing neurons was restricted to the hypothalamus and a few other regions, or whether it might exist throughout the brain, we examined the Ca2+ responses in cultured olfactory bulb, cortex, medulla, striatum, thalamus, hippocampus, and colliculus. The majority (75%) of developing neurons from each region showed a Ca2+ rise in response to GABA. Together these data suggest that GABA elevates Ca2+ in developing, but not mature, neurons from the hypothalamus and all other brain regions examined.
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