期刊
JOURNAL OF NEUROSCIENCE
卷 37, 期 46, 页码 11114-11126出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0351-17.2017
关键词
delayed spatial alternation; dorsal hippocampus; oligophrenin-1; prefrontal cortex; protein kinase A; spatial working memory
资金
- Agence Nationale de la Recherche [ANR-2010-BLAN-1434-01]
- program investissement d'avenir (Labex Brain)
Classical and systems genetics have identified wide networks of genes associated with cognitive and neurodevelopmental diseases. In parallel to deciphering the role of each of these genes in neuronal or synaptic function, evaluating the response of neuronal and molecular networks to gene loss of function could reveal some pathophysiological mechanisms potentially accessible to nongenetic therapies. Loss of function of the Rho-GAP oligophrenin-1 is associated with cognitive impairments in both human and mouse. Upregulation of both PKA and ROCK has been reported in Ophn(-/y) mice, but it remains unclear whether kinase hyperactivity contributes to the behavioral phenotypes. In this study, we thoroughly characterized a prominent perseveration phenotype displayed by Ophn1-deficient mice using a Y-maze spatial working memory (SWM) test. We report that Ophn1 deficiency in the mouse generated severe cognitive impairments, characterized by both a high occurrence of perseverative behaviors and a lack of deliberation during the SWM test. In vivo and in vitro pharmacological experiments suggest that PKA dysregulation in the mPFC underlies cognitive dysfunction in Ophn1-deficient mice, as assessed using a delayed spatial alternation task results. Functionally, mPFC neuronal networks appeared to be affected in a PKAdependent manner, whereas hippocampal-PFC projections involved inSWMwere not affected in Ophn(-/y) mice. Thus, we propose that discrete gene mutations in intellectual disability might generate secondary pathophysiological mechanisms, which are prone to become pharmacological targets for curative strategies in adult patients.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据