Dysbindin modulates prefrontal cortical glutamatergic circuits and working memory function in mice.
Dysbindin modulates prefrontal cortical glutamatergic circuits and working memory function in mice.
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DOI：
10.1038/npp.2009.90
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发表时间：
2009-11
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影响因子：
--
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人类行为遗传学研究表明，DTNBP 1基因变异与精神分裂症及其认知缺陷表型相关。由DTNBP 1编码的蛋白质dysbindin在前脑神经元内表达，在那里它与参与囊泡运输和胞吐的蛋白质相互作用。为了进一步描述与dysbindin表达减少相关的细胞、生理和行为表型，我们在dtnbp 1基因内携带无效突变的小鼠中进行了研究。与野生型对照组相比，Dysbindin突变体表现出空间工作记忆障碍;杂合子小鼠表现出中等水平的认知功能障碍。记录在突变小鼠的前额叶皮层的深层锥体神经元表现出减少成对脉冲易化，诱发和微型兴奋性突触后电流，表明突触前神经元能终端的功能的差异，以及升高的尖峰阈值。两者合计，这些数据表明，dysbindin有效地调节兴奋性传递在前额叶皮层，可能通过突触前机制，并因此调节认知功能取决于这个大脑区域，提供新的见解的分子机制皮质功能障碍的精神分裂症。
Behavioral genetic studies of humans have associated variation in the DTNBP1 gene with schizophrenia and its cognitive deficit phenotypes. The protein coded for by DTNBP1, dysbindin, is expressed within forebrain glutamatergic neurons, where it interacts with proteins involved in vesicular trafficking and exocytosis. In order to further delineate the cellular, physiological and behavioral phenotypes associated with reduced dysbindin expression, we conducted studies in mice carrying a null mutation within the dtnbp1 gene. Dysbindin mutants exhibited impairments of spatial working memory as compared with wild-type controls; heterozygous mice exhibited intermediate levels of cognitive dysfunction. Deep layer pyramidal neurons recorded in the prefrontal cortex of mutant mice exhibited reductions in paired-pulse facilitation, and evoked and miniature excitatory post-synaptic currents, indicating a difference in the function of pre-synaptic glutamatergic terminals, as well as elevated spike thresholds. Taken together, these data indicate that dysbindin potently regulates excitatory transmission in prefrontal cortex, potentially through a pre-synaptic mechanism, and consequently modulates cognitive functions depending upon this brain region, providing new insights into the molecular mechanisms underlying cortical dysfunction in schizophrenia.
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DOI：
10.1111/j.1601-183x.2009.00477.x
发表时间：
2009-06
期刊：
Genes, brain, and behavior
影响因子：
--
作者：
Cox MM;Tucker AM;Tang J;Talbot K;Richer DC;Yeh L;Arnold SE
通讯作者：
Arnold SE
影响因子：
2.5
作者：
Compte, A;Constantinidis, C;Wang, WJ
通讯作者：
Wang, WJ
影响因子：
56.9
作者：
FUSTER, JM;ALEXANDER, GE
通讯作者：
ALEXANDER, GE
影响因子：
--
作者：
Cannon, TD;Hennah, W;Peltonen, L
通讯作者：
Peltonen, L
影响因子：
3.5
作者：
Burdick, KE;Lencz, T;Malhotra, AK
通讯作者：
Malhotra, AK