Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
Biochem Pharmacol. 2019 Oct;168:204-213. doi: 10.1016/j.bcp.2019.07.007. Epub 2019 Jul 8.
Impulsivity is a multifaceted behavioral manifestation with implications in several neuropsychiatric disorders. Glutamate neurotransmission through the N-methyl-D-aspartate receptors (NMDARs) in the medial prefrontal cortex (mPFC), an important brain region in decision-making and goal-directed behaviors, plays a key role in motor impulsivity. We discovered that inherent motor impulsivity predicted responsiveness to D-cycloserine (DCS), a partial NMDAR agonist, which prompted the hypothesis that inherent motor impulsivity is associated with the pattern of expression of cortical NMDAR subunits (GluN1, GluN2A, GluN2B), specifically the protein levels and synaptosomal trafficking of the NMDAR subunits. Outbred male Sprague-Dawley rats were identified as high (HI) or low (LI) impulsive using the one-choice serial reaction time task. Following phenotypic identification, mPFC synaptosomal protein was extracted from HI and LI rats to assess the expression pattern of the NMDAR subunits. Synaptosomal trafficking and stabilization for the GluN2 subunits were investigated by co-immunoprecipitation for postsynaptic density 95 (PSD95) and synapse associated protein 102 (SAP102). HI rats had lower mPFC GluN1 and GluN2A, but higher GluN2B and pGluN2B synaptosomal protein expression versus LI rats. Further, higher GluN2B:PSD95 and GluN2B:SAP102 protein:protein interactions were detected in HI versus LI rats. Thus, the mPFC NMDAR subunit expression pattern and/or synaptosomal trafficking associates with high inherent motor impulsivity. Increased understanding of the complex regulation of NMDAR balance within the mPFC as it relates to inherent motor impulsivity may lead to a better understanding of risk factors for impulse-control disorders.
冲动是一种多方面的行为表现，与多种神经精神疾病有关。在决策和目标导向行为的重要脑区——内侧前额叶皮层（mPFC）中，通过 N-甲基-D-天冬氨酸受体（NMDAR）的谷氨酸能神经传递，在运动冲动中起着关键作用。我们发现，固有运动冲动性预测了对 D-环丝氨酸（DCS）的反应性，DCS 是一种部分 NMDAR 激动剂，这促使我们假设固有运动冲动性与皮质 NMDAR 亚基（GluN1、GluN2A、GluN2B）的表达模式有关，特别是 NMDAR 亚基的蛋白水平和突触小体运输。使用一次性序列反应时间任务，将杂交雄性 Sprague-Dawley 大鼠鉴定为高（HI）或低（LI）冲动性。在表型鉴定后，从 HI 和 LI 大鼠中提取 mPFC 突触小体蛋白，以评估 NMDAR 亚基的表达模式。通过与突触后密度 95（PSD95）和突触相关蛋白 102（SAP102）的共免疫沉淀研究 GluN2 亚基的突触小体运输和稳定性。与 LI 大鼠相比，HI 大鼠的 mPFC GluN1 和 GluN2A 水平较低，但 GluN2B 和 pGluN2B 突触小体蛋白表达水平较高。此外，在 HI 大鼠中检测到更高的 GluN2B:PSD95 和 GluN2B:SAP102 蛋白-蛋白相互作用。因此，mPFC NMDAR 亚基表达模式和/或突触小体运输与高固有运动冲动性有关。更好地了解 mPFC 内 NMDAR 平衡的复杂调节与其固有运动冲动性的关系，可能有助于更好地理解冲动控制障碍的危险因素。
