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Dysbindin-1 通过多巴胺/D2 途径调节前额叶皮层活动和类似精神分裂症的行为。

Dysbindin-1 modulates prefrontal cortical activity and schizophrenia-like behaviors via dopamine/D2 pathways.

机构信息

Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute of Mental Health, Bethesda, MD 20892, USA.

出版信息

Mol Psychiatry. 2012 Jan;17(1):85-98. doi: 10.1038/mp.2010.106. Epub 2010 Oct 19.

DOI:10.1038/mp.2010.106
PMID:20956979
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3388848/
Abstract

Dysbindin-1 regulates D2-receptor trafficking and is implicated in schizophrenia and related cognitive abnormalities, but whether this molecular effect mediates the clinical manifestations of the disorder is unknown. We explored in dysbindin-1-deficient mice (dys-/-) (1) schizophrenia-related behaviors, (2) molecular and electrophysiological changes in medial prefrontal cortex (mPFC) and (3) the dependence of these on D2-receptor stimulation. Dysbindin-1 disruption altered dopamine-related behaviors and impaired working memory under challenging/stressful conditions. Dys-/- pyramidal neurons in mPFC layers II/III were hyperexcitable at baseline but hypoexcitable following D2 stimulation. Dys-/- were also respectively more and less sensitive to D2 agonist- and antagonist-induced behavioral effects. Dys-/- had reduced expression of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and CaMKKβ in mPFC. Chronic D2 agonist treatment reproduced these changes in protein expression, and some of the dys-/- behavioral effects. These results elucidate dysbindin's modulation of D2-related behavior, cortical activity and mPFC CaMK components, implicating cellular and molecular mechanisms of the association of dysbindin with psychosis.

摘要

Dysbindin-1 调节 D2 受体转运，与精神分裂症和相关认知异常有关，但这种分子效应是否介导该疾病的临床表现尚不清楚。我们在 dysbindin-1 缺陷型小鼠（dys-/-）中探索了（1）与精神分裂症相关的行为，（2）中前额叶皮层（mPFC）的分子和电生理变化，以及（3）这些变化对 D2 受体刺激的依赖性。Dysbindin-1 缺失改变了多巴胺相关行为，并在具有挑战性/应激条件下损害工作记忆。mPFC 层 II/III 中的 dys-/- 锥体神经元在基线时过度兴奋，但在 D2 刺激后兴奋性降低。dys-/- 对 D2 激动剂和拮抗剂诱导的行为效应的敏感性也分别更高和更低。dys-/- 在前额叶皮层中的 Ca(2+)/钙调蛋白依赖性蛋白激酶 II（CaMKII）和 CaMKKβ的表达减少。慢性 D2 激动剂处理再现了这些蛋白表达的变化，以及一些 dys-/- 行为效应。这些结果阐明了 dysbindin 对 D2 相关行为、皮层活动和 mPFC CaMK 成分的调节作用，提示 dysbindin 与精神病相关的细胞和分子机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c9/3388848/cc3d6ca88b0a/nihms-388224-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c9/3388848/f90a8bcbb858/nihms-388224-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c9/3388848/64f900c879e6/nihms-388224-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c9/3388848/03ed9db0fd73/nihms-388224-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c9/3388848/ab6cbaf97c7f/nihms-388224-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c9/3388848/cc3d6ca88b0a/nihms-388224-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c9/3388848/f90a8bcbb858/nihms-388224-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c9/3388848/64f900c879e6/nihms-388224-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c9/3388848/03ed9db0fd73/nihms-388224-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c9/3388848/ab6cbaf97c7f/nihms-388224-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c9/3388848/cc3d6ca88b0a/nihms-388224-f0005.jpg

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