Czéh Boldizsár, Vardya Irina, Varga Zsófia, Febbraro Fabia, Csabai Dávid, Martis Lena-Sophie, Højgaard Kristoffer, Henningsen Kim, Bouzinova Elena V, Miseta Attila, Jensen Kimmo, Wiborg Ove
Department of Clinical Medicine, Aarhus University, Risskov, Denmark.
Neurobiology of Stress Research Group, János Szentágothai Research Centre & Centre for Neuroscience, Pécs, Hungary.
Front Cell Neurosci. 2018 Jun 20;12:148. doi: 10.3389/fncel.2018.00148. eCollection 2018.
Clinical and experimental data suggest that fronto-cortical GABAergic deficits contribute to the pathophysiology of major depressive disorder (MDD). To further test this hypothesis, we used a well characterized rat model for depression and examined the effect of stress on GABAergic neuron numbers and GABA-mediated synaptic transmission in the medial prefrontal cortex (mPFC) of rats. Adult male Wistar rats were subjected to 9-weeks of chronic mild stress (CMS) and based on their hedonic-anhedonic behavior they were behaviorally phenotyped as being stress-susceptible (anhedonic) or stress-resilient. Post mortem quantitative histopathology was used to examine the effect of stress on parvalbumin (PV)-, calretinin- (CR), calbindin- (CB), cholecystokinin- (CCK), somatostatin-(SST) and neuropeptide Y-positive (NPY+) GABAergic neuron numbers in all cortical subareas of the mPFC (anterior cingulate (Cg1), prelimbic (PrL) and infralimbic (IL) cortexes). , whole-cell patch-clamp recordings from layer II-III pyramidal neurons of the ventral mPFC was used to examine GABAergic neurotransmission. The cognitive performance of the animals was assessed in a hippocampal-prefrontal-cortical circuit dependent learning task. Stress exposure reduced the number of CCK-, CR- and PV-positive GABAergic neurons in the mPFC, most prominently in the IL cortex. Interestingly, in the stress-resilient animals, we found higher number of neuropeptide Y-positive neurons in the entire mPFC. The electrophysiological analysis revealed reduced frequencies of spontaneous and miniature IPSCs in the anhedonic rats and decreased release probability of perisomatic-targeting GABAergic synapses and alterations in GABA receptor mediated signaling. In turn, pyramidal neurons showed higher excitability. Anhedonic rats were also significantly impaired in the object-place paired-associate learning task. These data demonstrate that long-term stress results in functional and structural deficits of prefrontal GABAergic networks. Our findings support the concept that fronto-limbic GABAergic dysfunctions may contribute to emotional and cognitive symptoms of MDD.
临床和实验数据表明，前额叶皮质γ-氨基丁酸能缺陷参与了重度抑郁症（MDD）的病理生理过程。为了进一步验证这一假设，我们使用了一种特征明确的大鼠抑郁模型，研究应激对大鼠内侧前额叶皮质（mPFC）中γ-氨基丁酸能神经元数量以及γ-氨基丁酸介导的突触传递的影响。成年雄性Wistar大鼠接受为期9周的慢性轻度应激（CMS），并根据其享乐-快感缺失行为将其行为表型分为应激易感性（快感缺失）或应激恢复性。死后定量组织病理学用于研究应激对mPFC所有皮质亚区（前扣带回（Cg1）、前额叶（PrL）和边缘下（IL）皮质）中帕瓦丁（PV）、钙视网膜蛋白（CR）、钙结合蛋白（CB）、胆囊收缩素（CCK）、生长抑素（SST）和神经肽Y阳性（NPY+）γ-氨基丁酸能神经元数量的影响。此外，使用腹侧mPFC II-III层锥体神经元的全细胞膜片钳记录来研究γ-氨基丁酸能神经传递。在海马-前额叶皮质回路依赖性学习任务中评估动物的认知表现。应激暴露减少了mPFC中CCK、CR和PV阳性γ-氨基丁酸能神经元的数量，最明显的是在IL皮质。有趣的是，在应激恢复性动物中，我们发现整个mPFC中神经肽Y阳性神经元的数量更多。电生理分析显示，快感缺失大鼠的自发性和微小抑制性突触后电流频率降低，躯体靶向性γ-氨基丁酸能突触的释放概率降低，以及γ-氨基丁酸受体介导的信号传导改变。反过来，锥体神经元表现出更高的兴奋性。快感缺失大鼠在物体-位置配对联想学习任务中也明显受损。这些数据表明，长期应激会导致前额叶γ-氨基丁酸能网络的功能和结构缺陷。我们的研究结果支持这样一种观点，即前额叶-边缘γ-氨基丁酸能功能障碍可能导致MDD的情绪和认知症状。
