以Akt1基因缺損小鼠為模式探討新生期特定GSK3抑制劑對於思覺失調症相關缺損之改善效果

Investigating the Effect of a Specific GSK3 Inhibitor During Neonatal Period on the Amelioration of Schizophrenia-Related Deficits in Akt1 Mutant Mouse Model of Schizophrenia

萬詩君(Shih-Chun Wan)

指導教授 ： 賴文崧

國立臺灣大學/理學院/心理學研究所/碩士(2020年)

https://doi.org/10.6342/NTU202002664

摘要

思覺失調症為嚴重的神經發展性疾病，致病機轉至今尚未全面了解，因此在治療此心理疾患仍充滿著諸多挑戰。從人類及動物的研究證據指出AKT1基因和思覺失調症的致病有關，且AKT/GSK3這條細胞訊息傳遞路徑也發現參與在思覺失調症的致病機轉中。GSK3為一種蛋白激酶參與在神經系統發育中，而其分子作用主要受到上游的蛋白激酶 — AKT所調控。研究顯示成年Akt1-/-老鼠對於抗精神疾病藥物的治療效果不佳，而GSK3抑制劑能有效治療成年Akt1-/-老鼠所展現出的類思覺失調症缺損。因此，本研究欲探討在新生兒時期給予SB-216763 (選擇性GSK3抑制劑)的治療模式是否能有效治癒成年Akt1+/-老鼠所展現出的類思覺失調症缺損。本研究進行了三個實驗分別從行為層次、生化層次、神經細胞型態層次去剖析此治療模式的效果。在實驗1中，此治療模式能有效地治療成年公母Akt1+/-老鼠所展現的長期記憶缺損。再者，此治療模式在成年公母Akt1+/-老鼠所展現於線索及情境的連結記憶缺損有治療效果。在實驗2中，此治療模式在出生後27天大的Akt1+/-老鼠其海馬的GSK3抑制效果有性別差異，公Akt1+/-老鼠在海馬的GSK3β沒有抑制效果，而母Akt1+/-老鼠在海馬的GSK3α有抑制效果。在實驗3中, 此治療模式被發現能有效的修復成年母Akt1+/-老鼠所展現於海馬CA1區域的椎狀神經細胞其基底樹突複雜度的缺損，而在成年公Akt1+/-老鼠則無效果。綜合以上結果，本研究推測新生兒期給予的SB-216763透過在新生兒期間不同程度的GSK3抑制效果而達到在成年Akt1+/-老鼠所展現出對於此治療效果於認知及神經細胞型態缺損上的性別差異。最後，本研究支持了此治療模式對於Akt1 基因缺損所展現出其相關思覺失調症狀的治療潛力。

關鍵字

思覺失調症 ； Akt1 ； GSK3抑制 ； AKT/GSK3細胞訊息傳遞路徑 ； 新生兒時期 ； SB-216763 ； 性別差異

並列摘要

Schizophrenia is a severe neurodevelopmental disorder with poorly understood, which remains a major challenge in the treatment of this mental disorder. Accumulating evidence from human and animal studies suggests that AKT1 contributes to susceptibility to schizophrenia and the AKT-GSK3 signaling pathway is involved in the pathogenesis of schizophrenia. GSK3, a key kinase modulating the development of the nervous system, is largely regulated by one of its upstream targets - AKT. Recent study showed that Akt1-/- mice were insensitive to antipsychotic drugs, and GSK3 inhibitors efficiently rescued the schizophrenia-like behaviors in adult Akt1-/- mice. Therefore, in this study, we aim to investigate whether the subchronic treatment with SB216763 (SB) (a selected GSK3 inhibitor) during neonatal period could rescue schizophrenia-related deficits in adult Akt1+/- mice. A series of experiments from three different approaches: behavior, biochemistry and neuromorphology were conducted. In experimental 1, this treatment had therapeutic effect on the aberrant long-term memory in both sexes of adult Akt1+/- mice. Moreover, this treatment rescued the deficits on associative memory with cue or context in both sexes of adult Akt1+/- mice. In experiment 2, this treatment elicited sex differences in the inhibition of GSK3 in the hippocampus of Akt1+/- mice at PND27, which male Akt1+/- mice had no effect of inhibition on hippocampal GSK3, and female Akt1+/- mice had the effect of inhibition on hippocampal GSK3α. In experiment 3, the effect of neonatal subchronic treatment with SB restored the reduction in basal dendritic complexity of the hippocampal CA1 pyramidal neurons of adult female Akt1+/- mice, while this treatment had no effect on basal dendritic complexity of the hippocampal CA1 pyramidal neurons in adult male Akt1+/- mice. Collectively, these results suggest that the neonatal subchronic treatment with SB exerts different levels of action on GSK3 inhibition to correct the dysfunction of AKT1/ GSK3 signaling pathway in different sexes of Akt1+/- mice at PND27, which leads to sex dependent therapeutic effect on adult Akt1+/- mice with cognitive impairments and impaired neuromorphology. Finding from this research supports the therapeutic effect of neonatal subchronic treatment with SB and its potential in the treatment of schizophrenia with Akt1 deficiency.

並列關鍵字

schizophrenia ； Akt1 ； GSK3 inhibition ； AKT/GSK3 signaling pathway ； neonatal period ； SB-216763 (SB) ； sex differences

參考文獻

Abel, K. M., Drake, R., Goldstein, J. M. (2010). Sex differences in schizophrenia. International Review of Psychiatry, 22(5), 417-428.

Aleman, A., Kahn, R. S., Selten, J.-P. (2003). Sex differences in the risk of schizophrenia: Evidence from meta-analysis. Archives of General Psychiatry, 60(6), 565-571. https://doi.org/10.1001/archpsyc.60.6.565

Alimohamad, H., Rajakumar, N., Seah, Y.-H., Rushlow, W. (2005). Antipsychotics alter the protein expression levels of β-catenin and GSK-3 in the rat medial prefrontal cortex and striatum. Biological Psychiatry, 57(5), 533-542.

Avishai-Eliner, S., Brunson, K. L., Sandman, C. A., Baram, T. Z. (2002). Stressed-out, or in (utero)? Trends in Neurosciences, 25(10), 518-524.

Bajestan, S. N., Sabouri, A. H., Nakamura, M., Takashima, H., Keikhaee, M. R., Behdani, F., Fayyazi, M. R., Sargolzaee, M. R., Bajestan, M. N., Sabouri, Z. (2006). Association of AKT1 haplotype with the risk of schizophrenia in Iranian population. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 141(4), 383-386.