Tzanoulinou Stamatina, García-Mompó Clara, Riccio Orbicia, Grosse Jocelyn, Zanoletti Olivia, Dedousis Panagiotis, Nacher Juan, Sandi Carmen
Department of Life Sciences, Laboratory of Behavioral Genetics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Neurobiology Unit and Program in Basic and Applied Neurosciences, Cell Biology Department, Universitat de València, Valencia, Spain.
Neuropsychopharmacology. 2016 Feb;41(3):751-61. doi: 10.1038/npp.2015.200. Epub 2015 Jul 8.
Emerging evidence indicates that attention deficits, which are frequently observed as core symptoms of neuropsychiatric disorders, may be elicited by early life stress. However, the mechanisms mediating these stress effects remain unknown. The prefrontal cortex (PFC) has been implicated in the regulation of attention, including dysfunctions in GABAergic transmission, and it is highly sensitive to stress. Here, we investigated the involvement of neuroligin-2 (NLGN-2), a synaptic cell adhesion molecule involved in the stabilization and maturation of GABAergic synapses, in the PFC in the link between stress and attention deficits. First, we established that exposure of rats to stress during the peripubertal period impairs attention in the five-choice serial reaction time task and results in reductions in the GABA-synthesizing enzyme glutamic acid decarboxylase in different PFC subregions (ie, prelimbic (PL), infralimbic, and medial and ventral orbitofrontal (OFC) cortex) and in NLGN-2 in the PL cortex. In peripubertally stressed animals, NLGN-2 expression in the PL and OFC cortex correlated with attention measurements. Subsequently, we found that adeno-associated virus-induced rescue of NLGN-2 in the PFC reverses the stress-induced attention deficits regarding omitted trials. Therefore, our findings highlight peripuberty as a period that is highly vulnerable to stress, leading to the development of attention deficits and a dysfunction in the PFC GABAergic system and NLGN-2 expression. Furthermore, NLGN-2 is underscored as a promising target to treat stress-induced cognitive alterations, and in particular attentional deficits as manifested by augmented omissions in a continuous performance task.
新出现的证据表明,注意力缺陷作为神经精神疾病的核心症状经常被观察到,可能是由早期生活压力引起的。然而,介导这些压力效应的机制仍然未知。前额叶皮层(PFC)参与注意力调节,包括γ-氨基丁酸(GABA)能传递功能障碍,并且它对压力高度敏感。在这里,我们研究了神经连接蛋白-2(NLGN-2),一种参与GABA能突触稳定和成熟的突触细胞粘附分子,在前额叶皮层中应激与注意力缺陷之间联系中的作用。首先,我们确定青春期前后大鼠暴露于应激会损害其在五选择连续反应时任务中的注意力,并导致不同前额叶皮层亚区(即前边缘区(PL)、边缘下区、内侧和腹侧眶额叶(OFC)皮层)中GABA合成酶谷氨酸脱羧酶以及PL皮层中NLGN-2的减少。在青春期前后受到应激的动物中,PL和OFC皮层中NLGN-2的表达与注意力测量值相关。随后,我们发现腺相关病毒介导的前额叶皮层中NLGN-2的挽救可逆转应激诱导的关于遗漏试验的注意力缺陷。因此,我们的研究结果突出了青春期前后是一个极易受到压力影响的时期,会导致注意力缺陷的发展以及前额叶皮层GABA能系统和NLGN-2表达的功能障碍。此外,NLGN-2被强调为治疗应激诱导的认知改变,特别是在持续操作任务中因遗漏增加所表现出的注意力缺陷的一个有前景的靶点。