Burket Jessica A, Benson Andrew D, Green Torrian L, Rook Jerri M, Lindsley Craig W, Conn P Jeffrey, Deutsch Stephen I
Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, Norfolk, VA, United States.
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, United States.
Prog Neuropsychopharmacol Biol Psychiatry. 2015 Aug 3;61:10-7. doi: 10.1016/j.pnpbp.2015.03.003. Epub 2015 Mar 14.
The NMDA receptor is a highly regulated glutamate-gated cationic channel receptor that has an important role in the regulation of sociability and cognition. The genetically-inbred Balb/c mouse has altered endogenous tone of NMDA receptor-mediated neurotransmission and is a model of impaired sociability, relevant to Autism Spectrum Disorders (ASDs). Because glycine is an obligatory co-agonist that works cooperatively with glutamate to promote opening of the ion channel, one prominent strategy to promote NMDA receptor-mediated neurotransmission involves inhibition of the glycine type 1 transporter (GlyT1). The current study evaluated the dose-dependent effects of VU0410120, a selective, high-affinity competitive GlyT1 inhibitor, on measures of sociability, cognition and stereotypic behaviors in Balb/c and Swiss Webster mice. The data show that doses of VU0410120 (i.e., 18 and 30mg/kg) that improve measures of sociability and spatial working memory in the Balb/c mouse strain elicit intense stereotypic behaviors in the Swiss Webster comparator strain (i.e., burrowing and jumping). Furthermore, the data suggest that selective GlyT1 inhibition improves sociability and spatial working memory at doses that do not worsen or elicit stereotypic behaviors in a social situation in the Balb/c strain. However, the elicitation of stereotypic behaviors in the Swiss Webster comparator strain at therapeutically relevant doses of VU0410120 suggest that genetic factors (i.e., mouse strain differences) influence sensitivity to GlyT1-elicited stereotypic behaviors, and emergence of intense stereotypic behaviors may be dose-limiting side effects of this interventional strategy.
NMDA受体是一种受高度调控的谷氨酸门控阳离子通道受体，在社交能力和认知调节中发挥重要作用。基因近交系Balb/c小鼠的NMDA受体介导的神经传递内源性张力发生改变，是社交能力受损的模型，与自闭症谱系障碍（ASD）相关。由于甘氨酸是一种必需的协同激动剂，与谷氨酸协同作用促进离子通道开放，促进NMDA受体介导的神经传递的一个突出策略是抑制甘氨酸1型转运体（GlyT1）。本研究评估了选择性、高亲和力竞争性GlyT1抑制剂VU0410120对Balb/c和瑞士 Webster小鼠社交能力、认知和刻板行为指标的剂量依赖性影响。数据显示，能改善Balb/c小鼠品系社交能力和空间工作记忆的VU0410120剂量（即18和30mg/kg）在瑞士 Webster对照品系中引发强烈的刻板行为（即挖掘和跳跃）。此外，数据表明，在Balb/c品系中，选择性抑制GlyT1在不加重或引发社交情境中刻板行为的剂量下可改善社交能力和空间工作记忆。然而，在与治疗相关的VU0410120剂量下，瑞士 Webster对照品系中出现刻板行为表明遗传因素（即小鼠品系差异）影响对GlyT-1引发的刻板行为的敏感性，强烈刻板行为的出现可能是这种干预策略的剂量限制性副作用。
