Disrupted in schizophrenia 1 modulates medial prefrontal cortex pyramidal neuron activity through cAMP regulation of transient receptor potential C and small-conductance K+ channels.
Disrupted in schizophrenia 1 modulates medial prefrontal cortex pyramidal neuron activity through cAMP regulation of transient receptor potential C and small-conductance K+ channels.
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DOI：
10.1016/j.biopsych.2013.12.019
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发表时间：
2014-09-15
影响因子：
10.6
通讯作者：
Yeckel, Mark F.
中科院分区：
文献类型：
--
作者：
El-Hassar, Lynda;Simen, Arthur A.;Duque, Alvaro;Patel, Kiran D.;Kaczmarek, Leonard K.;Arnsten, Amy F. T.;Yeckel, Mark F.
精神分裂症1(DISC1)是一种与精神分裂症、双相情感障碍、严重抑郁障碍和自闭症有关的蛋白质。到目前为止，大多数研究DISC1功能的研究都集中在它在神经发育中的作用，尽管它存在于整个生命过程中。当cAMP浓度较高时，DISC1还通过增加cAMP的PDE4分解代谢来调节cAMP信号。在这项研究中，我们验证了DISC1通过其对cAMP的调节来调节I-SK和I-TRPC通道介导的离子电流的假说，我们已经证明了这些离子电流可以调节成熟的前额叶皮质锥体神经元的活动。我们在成年大鼠的前额叶皮质脑片上使用了膜片钳记录，其中DISC1功能在体内被shRNA病毒敲除或在体外通过DISC1抗体的透析而降低。我们发现，DISC1阻断导致mGluR诱导的细胞内钙波增加，SK介导的超极化和TRPC介导的持续去极化减少。与DISC1在cAMP信号调节中的作用一致，Forsklin诱导的cAMP产生也增加了细胞内钙波和I-SK，并降低了I-TRPC。最后，用去甲肾上腺素能激动剂α抑制cAMP的生成，使SK和TRPC通道的功能正常化。基于我们的发现，我们认为，DISC1功能的减弱，如某些精神障碍的发生，可以通过失去对mGluR介导的细胞内钙波、SK和TRPC通道活性的cAMP调节，导致PFC活动的正常模式的中断。
Disrupted in Schizophrenia 1 (DISC1) is a protein implicated in schizophrenia, bipolar disorder, major depressive disorder, and autism. To date, most of research examining DISC1 function has focused on its role in neurodevelopment, despite its presence throughout life. DISC1 also regulate cAMP signaling by increasing PDE4 catabolism of cAMP when cAMP concentrations are high. In this study, we tested the hypothesis that DISC1, through its regulation of cAMP, modulates I-SK and I-TRPC channel-mediated ionic currents that we have shown previously to regulate the activity of mature prefrontal cortical pyramidal neurons. We used patch-clamp recordings in prefrontal cortical slices from adult rats in which DISC1 function was reduced in vivo by shRNA viral knockdown or in vitro by dialysis of DISC1 antibodies. We found that DISC1 disruption resulted in an increase of: mGluR-induced intracellular Ca2+ waves, SK-mediated hyperpolarization and a decrease of TRPC-mediated sustained depolarization. Consistent with a role for DISC1 in regulation of cAMP signaling, forskolin-induced cAMP production also increased intracellular Ca2+ waves, I-SK and decreased I-TRPC. Lastly, inhibiting cAMP generation with guanfacine, an α2A-noradrenergic agonist, normalized the function of SK and TRPC channels. Based on our findings, we propose that diminished DISC1 function, such as occurs in some mental disorders, can lead to the disruption of normal patterns of PFC activity through the loss of cAMP regulation of mGluR-mediated intracellular Ca2+ waves, SK and TRPC channel activity.
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影响因子：
4
作者：
Hagenston AM;Rudnick ND;Boone CE;Yeckel MF
通讯作者：
Yeckel MF
影响因子：
34.7
作者：
Arnsten, Amy F. T.
通讯作者：
Arnsten, Amy F. T.
DOI：
10.1002/ajmg.b.10757
发表时间：
2003-01-01
影响因子：
2.8
作者：
Gasperoni, TL;Ekelund, J;Cannon, TD
通讯作者：
Cannon, TD
影响因子：
3.4
作者：
Franowicz, JS;Arnsten, AFT
通讯作者：
Arnsten, AFT
影响因子：
4.5
作者：
Broadbelt, K;Byne, W;Jones, LB
通讯作者：
Jones, LB