Pdxdc1 modulates prepulse inhibition of acoustic startle in the mouse.
Pdxdc1 modulates prepulse inhibition of acoustic startle in the mouse.
复制标题
PDXDC1调节小鼠中声学惊吓的预硫次抑制。
DOI：
10.1038/tp.2017.85
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发表时间：
2017-05-09
影响因子：
6.8
通讯作者：
Wong AHC
中科院分区：
文献类型：
--
作者：
Feldcamp LA;Boutros PC;Raymond R;Fletcher PJ;Nobrega JN;Wong AHC
目前用于治疗精神分裂症的抗精神病药物都以多巴胺D2受体为靶点。虽然这些药物具有严重的副作用和有限的疗效，但没有新的精神分裂症治疗分子靶点已成功转化为新的药物。为了确定精神分裂症的新的潜在治疗靶点，我们在小鼠中寻找以前未知的声学前脉冲抑制（PPI）（精神分裂症内表型）的分子调节剂。我们检查了6个具有一系列PPI的近交系小鼠品系，并使用微阵列来确定这些小鼠品系中哪些mRNA水平与PPI相关。我们检查了与PPI和精神分裂症相关的几个大脑区域：海马体、纹状体和脑干，发现了许多与PPI水平表现出良好相关性的转录本，并通过实时定量PCR证实了这一点。然后，我们选择了一个候选基因进行进一步的研究，Pdxdc 1（吡哆醛依赖性脱羧酶结构域包含1），因为它是一个假定的酶，可以代谢儿茶酚胺神经递质，因此可能是一个可行的目标，为新的药物。我们确定Pdxdc 1 mRNA和蛋白质在海马中均强烈表达，并且Pdxdc 1水平与六种小鼠品系的PPI呈负相关。使用包装在慢病毒载体中的shRNA，我们抑制了海马中的Pdxdc 1蛋白水平，并使PPI增加了70%。我们的研究结果表明，Pdxdc 1可以调节PPI，并可能是一个很好的目标，为进一步调查作为一个潜在的治疗精神分裂症。
Current antipsychotic medications used to treat schizophrenia all target the dopamine D2 receptor. Although these drugs have serious side effects and limited efficacy, no novel molecular targets for schizophrenia treatment have been successfully translated into new medications. To identify novel potential treatment targets for schizophrenia, we searched for previously unknown molecular modulators of acoustic prepulse inhibition (PPI), a schizophrenia endophenotype, in the mouse. We examined six inbred mouse strains that have a range of PPI, and used microarrays to determine which mRNA levels correlated with PPI across these mouse strains. We examined several brain regions involved in PPI and schizophrenia: hippocampus, striatum, and brainstem, found a number of transcripts that showed good correlation with PPI level, and confirmed this with real-time quantitative PCR. We then selected one candidate gene for further study, Pdxdc1 (pyridoxal-dependent decarboxylase domain containing 1), because it is a putative enzyme that could metabolize catecholamine neurotransmitters, and thus might be a feasible target for new medications. We determined that Pdxdc1 mRNA and protein are both strongly expressed in the hippocampus and levels of Pdxdc1 are inversely correlated with PPI across the six mouse strains. Using shRNA packaged in a lentiviral vector, we suppressed Pdxdc1 protein levels in the hippocampus and increased PPI by 70%. Our results suggest that Pdxdc1 may regulate PPI and could be a good target for further investigation as a potential treatment for schizophrenia.
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影响因子：
3.7
作者：
Fath S;Bauer AP;Liss M;Spriestersbach A;Maertens B;Hahn P;Ludwig C;Schäfer F;Graf M;Wagner R
通讯作者：
Wagner R
影响因子：
3.4
作者：
Porta, Silvia;Marti, Eulalia;Arbones, Maria L.
通讯作者：
Arbones, Maria L.
影响因子：
64.8
作者：
Hovatta, I;Tennant, RS;Barlow, C
通讯作者：
Barlow, C
影响因子：
3.5
作者：
Kim, Dong Hyun;Yoon, Byung Hoon;Ryu, Jong Hoon
通讯作者：
Ryu, Jong Hoon
影响因子：
11
作者：
Insel, TR;Scolnick, EM
通讯作者：
Scolnick, EM