Acid-sensing ion channels contribute to synaptic transmission and inhibit cocaine-evoked plasticity
Acid-sensing ion channels contribute to synaptic transmission and inhibit cocaine-evoked plasticity
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DOI：
10.1038/nn.3750
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发表时间：
2014-08-01
影响因子：
25
通讯作者：
Wemmie, John A.
中科院分区：
文献类型：
--
作者：
Kreple, Collin J.;Lu, Yuan;Wemmie, John A.
酸敏感离子通道1A(ASIC1A)在伏隔核(NAC)中含量丰富，该区域以其在成瘾中的作用而闻名。因为ASIC1A被建议促进联想学习，我们假设在NAC中干扰ASIC1A会减少与药物相关的学习和记忆。然而，与这一假设相反，我们发现干扰小鼠NAC中的ASIC1A增加了可卡因条件下的位置偏好，表明ASIC1A在成瘾相关行为中发挥了意想不到的作用。此外，在大鼠NAC中过表达ASIC1A减少了可卡因的自我给药。在对其潜在机制的研究中，我们发现了一种以前未知的突触后电流，它在神经传递过程中由ASIC1A和ASIC2介导，从而很好地调节突触的结构和功能。与这种可能性一致，扰乱ASIC1A改变了树突棘密度和谷氨酸受体功能，并增加了可卡因诱导的可塑性，这类似于以前与可卡因诱导的行为相关的变化。综上所述，这些数据表明，ASIC1A抑制了成瘾相关行为的可塑性，并提高了通过靶向ASIC依赖的神经传递来开发药物成瘾治疗的可能性。
Acid-sensing ion channel 1A (ASIC1A) is abundant in the nucleus accumbens (NAc), a region known for its role in addiction. Because ASIC1A has been suggested to promote associative learning, we hypothesized that disrupting ASIC1A in the NAc would reduce drug-associated learning and memory. However, contrary to this hypothesis, we found that disrupting ASIC1A in the mouse NAc increased cocaine-conditioned place preference, suggesting an unexpected role for ASIC1A in addiction-related behavior. Moreover, overexpressing ASIC1A in rat NAc reduced cocaine self-administration. Investigating the underlying mechanisms, we identified a previously unknown postsynaptic current during neurotransmission that was mediated by ASIC1A and ASIC2 and thus well positioned to regulate synapse structure and function. Consistent with this possibility, disrupting ASIC1A altered dendritic spine density and glutamate receptor function, and increased cocaine-evoked plasticity, which resemble changes previously associated with cocaine-induced behavior. Together, these data suggest that ASIC1A inhibits the plasticity underlying addiction-related behavior and raise the possibility of developing therapies for drug addiction by targeting ASIC-dependent neurotransmission.