Neuroplasticity and Behavior Unit, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Neuroplasticity and Behavior Unit, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Brain Behav Immun. 2015 Mar;45:60-70. doi: 10.1016/j.bbi.2014.10.010. Epub 2014 Oct 23.
Schizophrenia is associated with deficits in the hippocampus, a brain area important for learning and memory. The dentate gyrus (DG) of the hippocampus develops both before and after birth. To study the relative contribution of mature and adult-born DG granule cells to disease etiology, we compared both cell populations in a mouse model of psychiatric illness resulting from maternal immune activation. Polyriboinosinic-polyribocytidilic acid (PolyIC, 5mg/kg) or saline was given on gestation day 15 to pregnant female C57Bl/6 mice. Male offspring (n=105), was administered systemic bromodeoxyuridine (BrdU, 50mg/kg) (n=52) or intracerebral retroviral injection into the DG (n=53), to label dividing cells at one month of age. Two months later behavioral tests were performed to evaluate disease phenotype. Immunohistochemistry and whole-cell patch clamping were used to assess morphological and physiological characteristics of DG cells. Three-month-old PolyIC exposed male offspring exhibited deficient pre-pulse inhibition, spatial maze performance and motor coordination, as well as increased depression-like behavior. Histological analysis showed reduced DG volume and parvalbumin positive interneuron number. Both mature and new hippocampal neurons showed modifications in intrinsic properties such as increased input resistance and lower current threshold, and decreased action potential number. Reduced GABAergic inhibitory transmission was observed only in mature DG neurons. Differential impairments in mature DG cells and adult-born new neurons may have implications for behavioral deficits associated with maternal immune activation.
精神分裂症与海马体功能障碍有关，海马体是学习和记忆的重要区域。海马的齿状回（DG）在出生前后都有发育。为了研究成熟和成年新生 DG 颗粒细胞对疾病病因的相对贡献，我们在由母体免疫激活引起的精神疾病小鼠模型中比较了这两种细胞群体。聚肌胞苷酸（PolyIC，5mg/kg）或生理盐水在妊娠第 15 天给予 C57Bl/6 雌性小鼠。雄性后代（n=105），在一个月大时接受全身溴脱氧尿苷（BrdU，50mg/kg）（n=52）或脑内逆行病毒注入 DG（n=53），以标记分裂细胞。两个月后进行行为测试以评估疾病表型。免疫组织化学和全细胞膜片钳技术用于评估 DG 细胞的形态和生理特征。三个月大的 PolyIC 暴露雄性后代表现出前脉冲抑制不足、空间迷宫表现和运动协调能力下降，以及抑郁样行为增加。组织学分析显示 DG 体积和 Parvalbumin 阳性中间神经元数量减少。成熟和新生海马神经元的内在特性都发生了改变，例如增加了输入电阻和降低了电流阈值，并减少了动作电位数量。仅在成熟 DG 神经元中观察到 GABA 能抑制性传递减少。成熟 DG 细胞和成年新生神经元的不同损伤可能与母体免疫激活相关的行为缺陷有关。
