Translational Neuropharmacology, Section of Comparative Medicine, Yale University School of Medicine, 310 Cedar St., New Haven, CT, 06520, USA.
FORUM Pharmaceuticals, Inc., Waltham, MA, 02451, USA.
Alzheimers Res Ther. 2019 Oct 22;11(1):88. doi: 10.1186/s13195-019-0540-x.
Loss-of-function mutations in the progranulin gene cause frontotemporal dementia, a genetic, heterogeneous neurodegenerative disorder. Progranulin deficiency leads to extensive neuronal loss in the frontal and temporal lobes, altered synaptic connectivity, and behavioral alterations.
The chronological emergence of neurophysiological and behavioral phenotypes of Grn heterozygous and homozygous mice in the dorsomedial thalamic-medial prefrontal cortical pathway were evaluated by in vivo electrophysiology and reward-seeking/processing behavior, tested between ages 3 and 12.5 months.
Electrophysiological recordings identified a clear age-dependent deficit in the thalamocortical circuit. Both heterozygous and homozygous mice exhibited impaired input-output relationships and paired-pulse depression, but evoked response latencies were only prolonged in heterozygotes. Furthermore, we demonstrate firstly an abnormal reward-seeking/processing behavior in the homozygous mice which correlates with previously reported neuroinflammation.
Our findings indicate that murine progranulin deficiency causes age-dependent neurophysiological and behavioral abnormalities thereby indicating their validity in modeling aspects of human frontotemporal dementia.
颗粒蛋白前体基因的功能丧失突变会导致额颞叶痴呆，这是一种遗传的、异质性的神经退行性疾病。颗粒蛋白缺乏会导致额极和颞极的广泛神经元丧失、突触连接改变以及行为改变。
通过在体电生理学和奖励寻求/处理行为评估 Grn 杂合子和纯合子小鼠背内侧丘脑-内侧前额皮质通路中神经生理和行为表型的出现顺序，测试年龄在 3 至 12.5 个月之间。
电生理记录显示，丘脑皮质回路存在明显的年龄依赖性缺陷。杂合子和纯合子小鼠均表现出输入-输出关系和成对脉冲抑制受损，但只有杂合子的诱发反应潜伏期延长。此外，我们首次证明了纯合子小鼠的异常奖励寻求/处理行为与先前报道的神经炎症有关。
我们的发现表明，鼠类颗粒蛋白缺乏会导致年龄依赖性的神经生理和行为异常，从而表明它们在模拟人类额颞叶痴呆方面具有有效性。
