Feldcamp L A, Boutros P C, Raymond R, Fletcher P J, Nobrega J N, Wong A H C
Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
Campbell Family Mental Health Research Institute, The Centre for Addiction and Mental Health, Toronto, ON, Canada.
Transl Psychiatry. 2017 May 9;7(5):e1125. doi: 10.1038/tp.2017.85.
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.
目前用于治疗精神分裂症的抗精神病药物均作用于多巴胺D2受体。尽管这些药物有严重的副作用且疗效有限,但尚未有针对精神分裂症治疗的新分子靶点成功转化为新药物。为了确定精神分裂症的新潜在治疗靶点,我们在小鼠中寻找先前未知的听觉前脉冲抑制(PPI,一种精神分裂症内表型)的分子调节剂。我们检测了六种具有不同PPI水平的近交系小鼠,并使用微阵列来确定哪些mRNA水平与这些小鼠品系中的PPI相关。我们检测了几个与PPI和精神分裂症相关的脑区:海马体、纹状体和脑干,发现了一些与PPI水平有良好相关性的转录本,并通过实时定量PCR进行了验证。然后我们选择了一个候选基因进行进一步研究,即Pdxdc1(含吡哆醛依赖性脱羧酶结构域1),因为它是一种可能代谢儿茶酚胺神经递质的酶,因此可能是新药物的一个可行靶点。我们确定Pdxdc1 mRNA和蛋白在海马体中均强烈表达,并且在六种小鼠品系中Pdxdc1的水平与PPI呈负相关。使用包装在慢病毒载体中的shRNA,我们抑制了海马体中Pdxdc1蛋白的水平,并使PPI增加了70%。我们的结果表明,Pdxdc1可能调节PPI,并且作为精神分裂症潜在治疗方法,它可能是进一步研究的良好靶点。