Jiang Anlong, Wang Le, Lu Justin Y D, Freeman Amy, Campbell Charlie, Su Ping, Wong Albert H C, Liu Fang
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada.
Department of Pharmacology, University of Toronto, Toronto, ON M5S 1A8, Canada.
Brain Sci. 2021 Oct 24;11(11):1398. doi: 10.3390/brainsci11111398.
Fragile X syndrome (FXS) is an X-chromosome-linked dominant genetic disorder that causes a variable degree of cognitive dysfunction and developmental disability. Current treatment is symptomatic and no existing medications target the specific cause of FXS. As with other X-linked disorders, FXS manifests differently in males and females, including abnormalities in the dopamine system that are also seen in -knockout (KO) mice. We investigated sex differences in dopamine signaling in -KO mice in response to L-stepholidine, a dopamine D1 receptor agonist and D2 receptor antagonist. We found significant sex differences in basal levels of phosphorylated protein kinase A (p-PKA) and glycogen synthase kinase (GSK)-3β in wild type mice that were absent in -KO mice. In wild-type mice, L-stepholidine increased p-PKA in males but not female mice, decreased p-GSK-3 in female mice and increased p-GSK-3 in male mice. Conversely, in -KO mice, L-stepholidine increased p-PKA and p-GSK-3β in females, and decreased p-PKA and p-GSK-3β in males.
脆性X综合征（FXS）是一种X染色体连锁的显性遗传病，可导致不同程度的认知功能障碍和发育残疾。目前的治疗是对症治疗，现有的药物均未针对FXS的具体病因。与其他X连锁疾病一样，FXS在男性和女性中的表现不同，包括多巴胺系统的异常，这在基因敲除（KO）小鼠中也可见。我们研究了KO小鼠对多巴胺D1受体激动剂和D2受体拮抗剂L-千金藤啶碱反应时多巴胺信号传导的性别差异。我们发现野生型小鼠中磷酸化蛋白激酶A（p-PKA）和糖原合酶激酶（GSK）-3β的基础水平存在显著性别差异，而在KO小鼠中不存在这种差异。在野生型小鼠中，L-千金藤啶碱增加了雄性小鼠而非雌性小鼠的p-PKA，降低了雌性小鼠的p-GSK-3并增加了雄性小鼠的p-GSK-3。相反，在KO小鼠中，L-千金藤啶碱增加了雌性小鼠的p-PKA和p-GSK-3β，并降低了雄性小鼠的p-PKA和p-GSK-3β。
