Alter Shawn P, Stout Kristen A, Lohr Kelly M, Taylor Tonya N, Shepherd Kennie R, Wang Minzheng, Guillot Thomas S, Miller Gary W
Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, United States.
Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, United States; Center for Neurodegenerative Disease, School of Medicine, Emory University, Atlanta, GA, United States.
Exp Neurol. 2016 Jan;275 Pt 1(Pt 1):17-24. doi: 10.1016/j.expneurol.2015.09.016. Epub 2015 Sep 30.
We previously demonstrated that mice with reduced expression of the vesicular monoamine transporter 2 (VMAT2 LO) undergo age-related degeneration of the catecholamine-producing neurons of the substantia nigra pars compacta and locus ceruleus and exhibit motor disturbances and depressive-like behavior. In this work, we investigated the effects of reduced vesicular transport on the function and viability of serotonin neurons in these mice. Adult (4-6 months of age), VMAT2 LO mice exhibit dramatically reduced (90%) serotonin release capacity, as measured by fast scan cyclic voltammetry. We observed changes in serotonin receptor responsivity in in vivo pharmacological assays. Aged (months) VMAT2 LO mice exhibited abolished 5-HT1A autoreceptor sensitivity, as determined by 8-OH-DPAT (0.1 mg/kg) induction of hypothermia. When challenged with the 5HT2 agonist, 2,5-dimethoxy-4-iodoamphetamine (1 mg/kg), VMAT2 LO mice exhibited a marked increase (50%) in head twitch responses. We observed sparing of serotonergic terminals in aged mice (18-24 months) throughout the forebrain by SERT immunohistochemistry and [(3)H]-paroxetine binding in striatal homogenates of aged VMAT2 LO mice. In contrast to their loss of catecholamine neurons of the substantia nigra and locus ceruleus, aged VMAT2 LO mice do not exhibit a change in the number of serotonergic (TPH2+) neurons within the dorsal raphe, as measured by unbiased stereology at 26-30 months. Collectively, these data indicate that reduced vesicular monoamine transport significantly disrupts serotonergic signaling, but does not drive degeneration of serotonin neurons.
我们先前证明，囊泡单胺转运体2表达降低的小鼠（VMAT2 LO）会经历黑质致密部和蓝斑中产生儿茶酚胺的神经元的年龄相关性退化，并表现出运动障碍和抑郁样行为。在这项工作中，我们研究了囊泡转运减少对这些小鼠中血清素神经元功能和活力的影响。成年（4 - 6个月大）的VMAT2 LO小鼠表现出显著降低（90%）的血清素释放能力，这通过快速扫描循环伏安法测量得出。我们在体内药理学实验中观察到血清素受体反应性的变化。老年（月龄）VMAT2 LO小鼠表现出5-HT1A自身受体敏感性丧失，这通过8 - OH - DPAT（0.1 mg/kg）诱导体温过低来确定。当用5HT2激动剂2,5 - 二甲氧基 - 4 - 碘苯丙胺（1 mg/kg）进行刺激时，VMAT2 LO小鼠的头部抽搐反应显著增加（50%）。通过SERT免疫组织化学和老年VMAT2 LO小鼠纹状体匀浆中的[³H] - 帕罗西汀结合，我们观察到老年小鼠（18 - 24个月）前脑血清素能终末得以保留。与黑质和蓝斑中儿茶酚胺神经元的丧失形成对比的是，在26 - 30个月时通过无偏立体学测量，老年VMAT2 LO小鼠背侧中缝核内血清素能（TPH2 +）神经元的数量没有变化。总体而言，这些数据表明囊泡单胺转运减少会显著扰乱血清素能信号传导，但不会导致血清素神经元退化。
