Pharmacological protection of synaptic function, spatial learning, and memory from transient hypoxia in rats
Pharmacological protection of synaptic function, spatial learning, and memory from transient hypoxia in rats
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DOI：
10.1124/jpet.300.2.408
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发表时间：
2002-02-01
影响因子：
3.5
通讯作者：
Alkon, DL
中科院分区：
文献类型：
--
作者：
Sun, MK;Xu, H;Alkon, DL
缺氧显着降低了大鼠CA 1区的胆碱能theta活动和海马切片中记录的CA 1锥体细胞的细胞内theta。海马CA 1区锥体细胞对短暂缺氧的缺氧反应包括短暂的“突触停滞”，观察到电压钳下兴奋性突触后电流的消除，并立即恢复氧合重新启动。缺氧性突触阻滞与锥体细胞对外源性L-谷氨酸的突触后反应降低无关，表明突触阻滞可能是突触前机制所致。腺苷A（1）受体拮抗剂8-环戊基-1，3-二丙基黄嘌呤（DPCPX）可消除缺氧性突触阻滞。阻断腺苷A（1）受体也消除了缺氧对海马CA 1区θ波活动和CA 1区锥体细胞内θ波的影响。在行为大鼠，短暂缺氧损害其水迷宫的表现在逃避潜伏期和探测测试。侧脑室注射DPCPX可防止这种损害。这些结果表明，缺氧释放腺苷，并产生对突触传递和参与海马CA 1 θ活性产生/维持的细胞内信号级联的抑制。这种通过腺苷A（1）受体拮抗作用对突触功效和空间学习的保护可能代表了一种有效的治疗策略，以消除由于短暂缺氧、发作和/或继发于呼吸功能损害的慢性缺氧引起的功能中断。
Hypoxia significantly reduced cholinergic theta activity in rat CA1 field and intracellular theta in the CA1 pyramidal cells, recorded in hippocampal slices. The hypoxic responses of the hippocampal CA1 pyramidal cells to a brief hypoxia consisted of a short period of "synaptic arrest", observed as an elimination of excitatory postsynaptic current under voltage clamp and recovered immediately as oxygenation was reinitiated. The hypoxic synaptic arrest was not associated with reduced postsynaptic responses of the pyramidal cells to externally applied L-glutamate, suggesting that the synaptic arrest might result from a presynaptic mechanism. The hypoxic synaptic arrest was abolished in the presence of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a specific adenosine A(1) receptor antagonist. Blocking adenosine A(1) receptors also eliminated effects of hypoxia on the hippocampal CA1 field theta activity and intracellular theta of the CA1 pyramidal cells. In behaving rats, brief hypoxia impaired their water maze performance in both the escape latency and probe tests. The impairment was prevented by intralateral cerebroventricular injections of DPCPX. These results suggest that hypoxia releases adenosine and produces an inhibition of synaptic transmission and intracellular signal cascade(s) involved in generation/maintenance of hippocampal CA1 theta activity. This protection of synaptic efficacy and spatial learning through adenosine A(1) receptor antagonism may represent an effective therapeutic strategy to eliminate functional interruption due to transient hypoxic, episodes and/or chronic hypoxia secondary to compromise of respiratory function.