Abstract
摘要:精神分裂症(schizophrenia)的盛行率在全世界人口中約為1%,是一種造成家庭與社會沉重負擔的重大精神疾患,但是目前對於其相關的致病機轉與可能成因仍然不清楚。從人類遺傳學及神經科學的研究中發現精神分裂症很可能是多基因遺傳的疾病,並發現AKT1及GABA-A受體基因是可能致病的危險因子之一,非常值得進一步深入研究。傳統的研究中通常僅能將病人依據其臨床症狀加以歸類,並用試誤法對病人施以藥物治療,但往往進展緩慢且成效有限,AKT1基因剔除小鼠則提供了一個相對可行的動物模式,去研究危險因子-AKT1在精神分裂症(特別是與人類相關之高等認知功能)上所扮演的角色及其作用機制,目前計畫與哥倫比亞大學Dr. Joseph Gogos合作,從哥大醫學中心引進剔除AKT1基因的小鼠,將針對以下幾個方向進行進一步的研究:1.探討AKT1缺損對精神分裂症相關行為與認知功能的影響;2.探討AKT1缺損對大腦神經組織與訊息傳導的影響;3.探討AKT1與精神分裂藥物的交互作用;4.研究大腦中AKT1與抑制性神經傳導物質GABA的交互作用與行為影響;5.在台大心理系建立行為神經科學核心實驗室提供教學及研究使用。
Abstract: Schizophrenia is a devastating psychiatric disorder and approximately 1 percent of the worldwide population develops schizophrenia during their lifetime. Schizophrenia is found all over the world, however, the etiology of schizophrenia is still unknown. Accumulating evidence from human genetics and neuroscience studies has started to merge and suggest several positional candidate loci and functional candidate genes, for example, V-AKT murine thymoma viral oncogene homolog 1 (AKT1) and GABA-A receptor subunit genes. AKT1, a schizophrenia susceptibility gene, is one of the 3 isoforms in the AKT (PKB) family (a serine/threonine kinase). There is accumulating evidence that AKT signaling plays a role in the pathogenesis of schizophrenia. Convergent evidence from human brains and animal studies have suggested that a decrease in Akt1 protein levels in the brains of schizophrenic patients and AKT is a key signaling intermediate downstream of dopamine receptor D2, the best-established target of antipsychotic drugs. Interestingly, an association between schizophrenia and Akt1 genetic variants has also been reported in a three large Caucasian family samples of European descent and Iranian population but not in family samples from Taiwan.
A diverse and convergent body of data suggests that prefrontal cortex (PFC) is central to the pathophysiology of schizophrenia. Working memory might be processed in PFC to control fundamental cognitive abilities. Previous work in animal models has shown that AKT activity correlates with and modulates the effect of dopamine transmission on sensorimotor gating and locomotor activity, two behaviors used to model positive disease symptoms in mice. Whether and how deficiency in Akt1 signaling affects higher cognitive functions in PFC is still unclear. Besides, dysfunction of cerebral cortex (especially PFC) and hippocampus in schizophrenia is also thought to include alteration in GABAergic, inhibitory neurotransmission. Convergent findings indicate that reduced GABA synthesis in the parvalbumin-containing subpopulation of inhibitory GABA neurons in the dorsolateral prefrontal cortex of individuals with schizophrenia and impairments in GABA-mediated inhibition may underlie the working memory impairments in schizophrenic patients. Interestingly, Akt-mediated phosphorylation increases the number of GABAARs on the plasma membrane surface, thereby increasing the receptor-mediated synaptic transmission in neurons and linking Akt to the regulation of synaptic strength. However, the mechanism underlying the regulation of Akt1 to GABAergic interneuron in the brain is still much unknown. Both Akt1 and GABA are plausible candidates in schizophrenia.
Animal models play an essential role in the investigation of the mechanisms underlying comple
Keyword(s)
精神分裂症
AKT1基因剔除小鼠
行為研究
認知功能
γ-丁氨基酪酸
schizophrenia
AKT1 knockout mice
behavioral study
cognitive function
GABA