DISINHIBITION OF HIPPOCAMPAL CA3 NEURONS INDUCED BY SUPPRESSION OF AN ADENOSINE-A(1) RECEPTOR-MEDIATED INHIBITORY TONUS - PRESYNAPTIC AND POSTSYNAPTIC COMPONENTS
DISINHIBITION OF HIPPOCAMPAL CA3 NEURONS INDUCED BY SUPPRESSION OF AN ADENOSINE-A(1) RECEPTOR-MEDIATED INHIBITORY TONUS - PRESYNAPTIC AND POSTSYNAPTIC COMPONENTS
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DOI：
10.1016/0306-4522(93)90006-2
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发表时间：
1993-12-01
期刊：
影响因子：
3.3
通讯作者：
TENBRUGGENCATE, G
中科院分区：
文献类型：
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作者：
ALZHEIMER, C;SUTOR, B;TENBRUGGENCATE, G
在体外对海马 CA3 神经元进行细胞内记录，以研究该大脑区域内源性产生的腺苷产生的抑制性张力。浓度高达 100 nM 的高选择性腺苷 A1 受体拮抗剂 1,3-二丙基-8-环戊基黄嘌呤的浴应用可诱导自发性和刺激诱发的癫痫样爆发放电。一旦诱导，1,3-二丙基-8-环戊基黄嘌呤诱发的癫痫样活动显然是不可逆转的，即使在长时间灌注无药溶液后也是如此。通过将切片与氨基-3-羟基-5-甲基-4-异恶唑丙酸受体拮抗剂6-氰基-7-硝基喹喔啉-2,3-二酮（10μM）预温育，但不与N-甲基-D-天冬氨酸受体拮抗剂D-2-氨基-5-磷酸戊酸（50μM）预温育，阻断谷氨酸兴奋性突触传递，阻止了诱导1,3-二丙基-8-环戊基黄嘌呤具有癫痫样活性。爆发放电的产生与膜电位无关，并且阵发性去极化转变的慢分量的幅度随着超极化而增加，表明1,3-二丙基-8-环戊基黄嘌呤诱导的爆发是突触介导的事件。河豚毒素处理的 CA3 神经元的记录揭示了内源性腺苷能抑制的强烈突触后成分。 1,3-二丙基-8-环戊基黄嘌呤和腺苷降解酶腺苷脱氨酶均产生约20 mV的明显不可逆的膜电位去极化。有时，这种去极化达到了产生假定的钙尖峰的阈值，但没有观察到类似于阵发性去极化转变事件的潜在变化。在电生理实验中使用的浓度 (30-100 nM) 下，1,3-二丙基-8-环戊基黄嘌呤对通过大鼠大脑匀浆中的放射化学测定测量的总环核苷酸磷酸二酯酶活性仅表现出可忽略不计的抑制作用皮质。此外，即使是高浓度的选择性磷酸二酯酶抑制剂咯利普兰（10μM），对腺苷受体没有亲和力，也不能模拟1,3-二丙基-8-环戊基黄嘌呤的电生理作用，因此排除了A1受体拮抗剂对神经元放电行为的影响可归因于磷酸二酯酶抑制的可能性。目前的数据表明，内源性释放的腺苷对神经元放电行为具有强有力的控制作用。海马 CA3 神经元突触前和突触后部位的兴奋性。腺苷能抑制短暂抑制后的长期去抑制强烈表明，除了众所周知的对神经元活动的短期影响外，腺苷还可能有助于海马兴奋性的长期控制。
Intracellular recordings were performed on hippocampal CA3 neurons in vitro to investigate the inhibitory tonus generated by endogenously produced adenosine in this brain region. Bath application of the highly selective adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine at concentrations up to 100 nM induced both spontaneous and stimulus-evoked epileptiform burst discharges. Once induced, the 1,3-dipropyl-8-cyclopentylxanthine-evoked epileptiform activity was apparently irreversible even after prolonged superfusion with drug-free solution. The blockade of glutamatergic excitatory synaptic transmission by preincubation of the slices with the amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (10 muM), but not with the N-methyl-D-aspartate receptor antagonist D-2-amino-5-phosphonovaleric acid (50 muM), prevented the induction of epileptiform activity by 1,3-dipropyl-8-cyclopentylxanthine. The generation of the burst discharges was independent of the membrane potential, and the amplitude of the slow component of the paroxysmal depolarization shift increased with hyperpolarization, indicating that the 1,3-dipropyl-8-cyclopentylxanthine-induced bursts were synaptically mediated events. Recordings from tetrodotoxin-treated CA3 neurons revealed a strong postsynaptic component of endogenous adenosinergic inhibition. Both 1,3-dipropyl-8-cyclopentylxanthine ard the adenosine-degrading enzyme adenosine deaminase produced an apparently irreversible depolarization of the membrane potential by about 20 mV. Sometimes, this depolarization attained the threshold for the generation of putative calcium spikes, but no potential changes resembling paroxysmal depolarization shift-like events were observed.At the concentrations used in electrophysiological experiments (30-100 nM), 1,3-dipropyl-8-cyclopentylxanthine displayed only a negligible inhibitory action on total cyclic nucleotide phosphodiesterase activity measured by means of a radiochemical assay in a homogenate of the rat cerebral cortex. Furthermore, even high concentrations of the selective phosphodiesterase inhibitor rolipram (10 muM), which displays no affinity to adenosine receptors, did not mimic the electrophysiological actions of 1,3-dipropyl-8-cyclopentylxanthine, thus excluding the possibility that the effects of the A1 receptor antagonist on neuronal discharge behavior can be ascribed to an inhibition of phosphodiesterases.The present data demonstrate that endogenously released adenosine exerts a vigorous control on the excitability of hippocampal CA3 neurons on both the pre- and postsynaptic sites. The long-lasting disinhibition following a transient suppression of adenosinergic inhibition strongly suggests that, besides its well-known short-term effects on neuronal activity, adenosine might also contribute to the long-term control of hippocampal excitability.