Abstract:
:Disrupted-in-Schizophrenia 1 (DISC1), a strong candidate gene for schizophrenia and other mental disorders, regulates neurodevelopmental processes including neurogenesis, neuronal migration, neurite outgrowth and spine development. Glycogen synthase kinase-3 (GSK3) directly interacts with DISC1 and also plays a role in neurodevelopment. Recently, our group showed that the Disc1-L100P mutant protein has reduced interaction with both GSK3α and β. Genetic and pharmacological inhibition of GSK3 activity rescued behavioral abnormalities in Disc1-L100P mutant mice. However, the cellular mechanisms mediating these effects of GSK3 inhibition in Disc1 mutant mice remain unclear. We sought to investigate the effects of genetic inactivation of GSK3α on frontal cortical neuron morphology in Disc1 L100P mutant mice using Golgi staining. We found a significant decrease in dendritic length and surface area in Disc1-L100P, GSK3α null and L100P/GSK3α double mutants. Dendritic spine density was significantly reduced only in Disc1-L100P and L100P/GSK3α +/- mice when compared to wild-type littermates. There was no difference in dendritic arborization between the various genotypes. No significant rescue in dendritic length and surface area was observed in L100P/GSK3α mutants versus L100P mice, but spine density in L100P/GSK3α mice was comparable to wild-type. Neurite outgrowth and spine development abnormalities induced by Disc1 mutation may be partially corrected through GSK3α inactivation, which also normalizes behavior. However, many of the other dendritic abnormalities in the Disc1-L100P mutant mice were not corrected by GSK3α inactivation, suggesting that only some of the anatomical defects have observable behavioral effects. These findings suggest novel treatment approaches for schizophrenia, and identify a histological read-out for testing other therapeutic interventions.
journal_name
Schizophr Resjournal_title
Schizophrenia researchauthors
Lee FH,Kaidanovich-Beilin O,Roder JC,Woodgett JR,Wong AHdoi
10.1016/j.schres.2011.03.032subject
Has Abstractpub_date
2011-06-01 00:00:00pages
74-9issue
1eissn
0920-9964issn
1573-2509pii
S0920-9964(11)00180-0journal_volume
129pub_type
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journal_title:Schizophrenia research
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pub_type: 杂志文章
doi:10.1016/j.schres.2012.09.007
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journal_title:Schizophrenia research
pub_type: 杂志文章
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journal_title:Schizophrenia research
pub_type: 杂志文章
doi:10.1016/s0920-9964(99)00045-6
更新日期:1999-11-30 00:00:00
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pub_type: 杂志文章
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更新日期:2010-08-01 00:00:00
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journal_title:Schizophrenia research
pub_type: 杂志文章
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journal_title:Schizophrenia research
pub_type: 杂志文章,随机对照试验
doi:10.1016/j.schres.2004.06.009
更新日期:2005-06-15 00:00:00
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pub_type: 杂志文章
doi:10.1016/0920-9964(94)90028-0
更新日期:1994-06-01 00:00:00
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journal_title:Schizophrenia research
pub_type: 杂志文章
doi:10.1016/j.schres.2013.11.023
更新日期:2014-01-01 00:00:00
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journal_title:Schizophrenia research
pub_type: 杂志文章,meta分析
doi:10.1016/j.schres.2006.08.021
更新日期:2007-01-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/j.schres.2017.04.001
更新日期:2018-02-01 00:00:00
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journal_title:Schizophrenia research
pub_type: 杂志文章
doi:10.1016/j.schres.2008.05.027
更新日期:2008-10-01 00:00:00
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journal_title:Schizophrenia research
pub_type: 杂志文章
doi:10.1016/j.schres.2006.07.006
更新日期:2006-12-01 00:00:00
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journal_title:Schizophrenia research
pub_type: 杂志文章
doi:10.1016/j.schres.2018.07.036
更新日期:2019-02-01 00:00:00
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journal_title:Schizophrenia research
pub_type: 临床试验,杂志文章,多中心研究
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pub_type: 杂志文章
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更新日期:2011-03-01 00:00:00
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journal_title:Schizophrenia research
pub_type: 杂志文章
doi:10.1016/j.schres.2011.03.034
更新日期:2011-08-01 00:00:00
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journal_title:Schizophrenia research
pub_type: 杂志文章
doi:10.1016/j.schres.2010.05.034
更新日期:2010-08-01 00:00:00
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journal_title:Schizophrenia research
pub_type: 杂志文章,评审
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更新日期:2017-08-01 00:00:00
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journal_title:Schizophrenia research
pub_type: 杂志文章
doi:10.1016/j.schres.2005.10.016
更新日期:2006-03-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/j.schres.2018.09.008
更新日期:2019-02-01 00:00:00
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journal_title:Schizophrenia research
pub_type: 杂志文章
doi:10.1016/0920-9964(92)90039-8
更新日期:1992-07-01 00:00:00
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journal_title:Schizophrenia research
pub_type: 杂志文章
doi:10.1016/j.schres.2010.03.012
更新日期:2010-07-01 00:00:00
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journal_title:Schizophrenia research
pub_type: 杂志文章
doi:10.1016/j.schres.2005.07.009
更新日期:2005-12-15 00:00:00
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pub_type: 杂志文章,评审
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更新日期:2017-12-01 00:00:00
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journal_title:Schizophrenia research
pub_type: 杂志文章,多中心研究
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更新日期:2015-04-01 00:00:00