Effects of acid-sensing ion channel-1A (ASIC1A) on cocaine-induced synaptic adaptations.
Effects of acid-sensing ion channel-1A (ASIC1A) on cocaine-induced synaptic adaptations.
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DOI：
10.3389/fphys.2023.1191275
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发表时间：
2023
影响因子：
4
通讯作者：
Wemmie, John A.
中科院分区：
文献类型：
--
作者：
Gupta, Subhash C.;Taugher-Hebl, Rebecca J.;Hardie, Jason B.;Fan, Rong;LaLumiere, Ryan T.;Wemmie, John A.
慢性药物滥用被认为会引起伏隔核中棘神经元（MSN）的突触变化，从而促进随后的渴望和寻求药物的行为。越来越多的数据表明酸敏离子通道 (ASIC) 可能发挥着关键作用。在未接受过药物治疗的小鼠中，破坏 ASIC1A 亚基会产生各种突触变化，让人想起可卡因戒断后的野生型小鼠，包括 AMPAR/NMDAR 比率增加、AMPAR 整流增加和树突棘密度增加。重要的是，Asic1a -/− 小鼠的这些变化通过单剂量的可卡因而正常化。在这里，我们试图了解可卡因暴露对 Asic1a −/− 小鼠的时间影响以及 ASIC1A 作用的细胞位点。接触可卡因六小时后，没有任何效果。然而，接触可卡因 15 小时、24 小时和 4 天后，Asic1a −/− 小鼠的 AMPAR/NMDAR 比率显着降低。 7 天内，AMPAR/NMDAR 比率恢复到基线水平。可卡因引起的 AMPAR 矫正和树突棘密度的变化遵循相似的时间过程，在 Asic1a −/− 小鼠中暴露于可卡因 24 小时后，矫正和树突棘密度显着减少。为了测试 ASIC1A 对这些反应的作用的细胞位点，我们专门在 MSN 亚群中破坏了 ASIC1A。我们发现 ASIC1A 破坏的影响是细胞自主的，并且仅限于通道被破坏的神经元。我们进一步测试了 ASIC1A 破坏是否对 MSN 亚型有差异性影响，发现 AMPAR/NMDAR 比率在表达多巴胺受体 1 的 MSN 中升高，表明对这些细胞有优先影响。最后，我们测试了蛋白质合成是否参与 ASIC1A 破坏后发生的突触适应，并发现蛋白质合成抑制剂茴香霉素使未接受药物的 Asic1a −/− 小鼠的 AMPAR 校正和 AMPAR/NMDAR 比率正常化至对照水平，在野生型小鼠中观察到。总之，这些结果为 ASIC 对突触可塑性和药物诱导效应的影响提供了有价值的机制见解，并提出了通过治疗操纵 ASIC1A 以对抗药物诱导的突触变化和行为的可能性。
Chronic drug abuse is thought to induce synaptic changes in nucleus accumbens medium spiny neurons (MSNs) that promote subsequent craving and drug-seeking behavior. Accumulating data suggest acid-sensing ion channels (ASICs) may play a critical role. In drug naïve mice, disrupting the ASIC1A subunit produced a variety of synaptic changes reminiscent of wild-type mice following cocaine withdrawal, including increased AMPAR/NMDAR ratio, increased AMPAR rectification, and increased dendrite spine density. Importantly, these changes in Asic1a −/− mice were normalized by a single dose of cocaine. Here we sought to understand the temporal effects of cocaine exposure in Asic1a −/− mice and the cellular site of ASIC1A action. Six hours after cocaine exposure, there was no effect. However, 15 h, 24 h and 4 days after cocaine exposure there was a significant reduction in AMPAR/NMDAR ratio in Asic1a −/− mice. Within 7 days the AMPAR/NMDAR ratio had returned to baseline levels. Cocaine-evoked changes in AMPAR rectification and dendritic spine density followed a similar time course with significant reductions in rectification and dendritic spines 24 h after cocaine exposure in Asic1a −/− mice. To test the cellular site of ASIC1A action on these responses, we disrupted ASIC1A specifically in a subpopulation of MSNs. We found that effects of ASIC1A disruption were cell autonomous and restricted to neurons in which the channels are disrupted. We further tested whether ASIC1A disruption differentially affects MSNs subtypes and found AMPAR/NMDAR ratio was elevated in dopamine receptor 1-expressing MSNs, suggesting a preferential effect for these cells. Finally, we tested if protein synthesis was involved in synaptic adaptations that occurred after ASIC1A disruption, and found the protein synthesis inhibitor anisomycin normalized AMPAR-rectification and AMPAR/NMDAR ratio in drug-naïve Asic1a −/− mice to control levels, observed in wild-type mice. Together, these results provide valuable mechanistic insight into the effects of ASICs on synaptic plasticity and drug-induced effects and raise the possibility that ASIC1A might be therapeutically manipulated to oppose drug-induced synaptic changes and behavior.
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影响因子：
5.3
作者：
Gonzalez-Inchauspe, Carlota;Urbano, Francisco J.;Uchitel, Osvaldo D.
通讯作者：
Uchitel, Osvaldo D.
影响因子：
25
作者：
Kreple, Collin J.;Lu, Yuan;Wemmie, John A.
通讯作者：
Wemmie, John A.
影响因子：
25
作者：
Loweth JA;Scheyer AF;Milovanovic M;LaCrosse AL;Flores-Barrera E;Werner CT;Li X;Ford KA;Le T;Olive MF;Szumlinski KK;Tseng KY;Wolf ME
通讯作者：
Wolf ME
DOI：
10.1073/pnas.1621185114
发表时间：
2017-02-07
影响因子：
11.1
作者：
Ceglia, Ilaria;Lee, Ko-Woon;Kim, Yong
通讯作者：
Kim, Yong
DOI：
10.1523/jneurosci.3625-11.2011
发表时间：
2011-10-12
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
McCutcheon JE;Loweth JA;Ford KA;Marinelli M;Wolf ME;Tseng KY
通讯作者：
Tseng KY