Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
School of Psychology, National University of Ireland, Galway, Ireland.
J Psychopharmacol. 2019 Dec;33(12):1610-1619. doi: 10.1177/0269881119875465. Epub 2019 Sep 26.
As exposure to stress has been linked to the onset and maintenance of psychotic illness, its pathogenesis may involve environmental stressors interacting with genetic vulnerability.
To establish whether acute stress interacts with a targeted mutation of the gene encoding the neurodevelopmental factor dystrobrevin-binding protein 1 (DTNBP1), resulting in a specific loss of the isoform dysbindin-1A, to influence schizophrenia-relevant phenotypes in mice during adolescence and adulthood.
Male and female mice with a heterozygous or homozygous deletion of DTNBP1 were assessed in the open field test following acute restraint stress in adolescence (Day 35) and young adulthood (Day 60-70). Effects of acute restraint stress on memory retention in the novel object recognition test was also assessed in adulthood. Baseline corticosterone was measured in serum samples and, brain-derived neurotrophic factor (BDNF), glucocorticoid and mineralocorticoid receptor gene expression levels were measured in the hippocampus of adult mice.
In the open field, deletion of dysbindin-1A induced hyperactivity and attenuated the action of stress to reduce hyperactivity in adolescence but not in adulthood; in females deletion of dysbindin-1A attenuated the effect of acute stress to increase anxiety-related behaviour in adolescence but not in adulthood. In the novel object recognition test, deletion of dysbindin-1A impaired memory and also revealed an increase in anxiety-related behaviour and a decrease in hippocampal BDNF gene expression in males.
These data suggest that deletion of dysbindin-1A influences behaviours related to schizophrenia and anxiety more robustly in adolescence than in adulthood and that dysbindin-1A influences stress-related responses in a sex-dependent manner.
由于暴露于压力与精神病的发病和维持有关，其发病机制可能涉及环境应激源与遗传易感性相互作用。
确定急性应激是否与编码神经发育因子肌营养不良蛋白结合蛋白 1（DTNBP1）的基因的靶向突变相互作用，导致特定的异源二聚体-1A 缺失，从而影响青春期和成年期小鼠的精神分裂症相关表型。
在青春期（第 35 天）和成年早期（第 60-70 天）急性束缚应激后，对携带 DTNBP1 杂合或纯合缺失的雄性和雌性小鼠进行旷场试验评估。还在成年期评估急性束缚应激对新物体识别试验中记忆保留的影响。在血清样本中测量基础皮质酮，并在成年小鼠的海马体中测量脑源性神经营养因子（BDNF）、糖皮质激素和盐皮质激素受体基因表达水平。
在旷场中，缺失异源二聚体-1A 诱导过度活跃，并减弱了应激减少青春期过度活跃的作用，但在成年期则没有；在雌性中，缺失异源二聚体-1A 减弱了急性应激增加青春期焦虑相关行为的作用，但在成年期则没有。在新物体识别试验中，缺失异源二聚体-1A 损害了记忆，并且还显示出焦虑相关行为增加和海马 BDNF 基因表达减少，仅在雄性中。
这些数据表明，缺失异源二聚体-1A 比成年期更强烈地影响青春期与精神分裂症和焦虑相关的行为，并且异源二聚体-1A 以性别依赖的方式影响应激相关反应。
