Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary; János Szentágothai School of Neurosciences, Semmelweis University School of PhD Studies, Budapest, Hungary.
Int J Neuropsychopharmacol. 2017 Oct 1;20(10):813-822. doi: 10.1093/ijnp/pyx046.
Major depressive disorder is characterized by structural and functional abnormalities of cortical and limbic brain areas, including a decrease in spine synapse number in the dentate gyrus of the hippocampus. Recent studies highlighted that both genetic and pharmacological invalidation of the purinergic P2X7 receptor (P2rx7) leads to antidepressant-like phenotype in animal experiments; however, the impact of P2rx7 on depression-related structural changes in the hippocampus is not clarified yet.
Effects of genetic deletion of P2rx7s on depressive-like behavior and spine synapse density in the dentate gyrus were investigated using the learned helplessness mouse model of depression.
We demonstrate that in wild-type animals, inescapable footshocks lead to learned helplessness behavior reflected in increased latency and number of escape failures to subsequent escapable footshocks. This behavior is accompanied with downregulation of mRNA encoding P2rx7 and decrease of spine synapse density in the dentate gyrus as determined by electron microscopic stereology. In addition, a decrease in synaptopodin but not in PSD95 and NR2B/GluN2B protein level was also observed under these conditions. Whereas the absence of P2rx7 was characterized by escape deficit, no learned helpless behavior is observed in these animals. Likewise, no decrease in spine synapse number and synaptopodin protein levels was detected in response to inescapable footshocks in P2rx7-deficient animals.
Our findings suggest the endogenous activation of P2rx7s in the learned helplessness model of depression and decreased plasticity of spine synapses in P2rx7-deficient mice might explain the resistance of these animals to repeated stressful stimuli.
重度抑郁症的特征是皮质和边缘脑区的结构和功能异常，包括海马齿状回的树突棘突触数量减少。最近的研究强调，嘌呤能 P2X7 受体（P2rx7）的遗传和药理学失活都导致动物实验中的抗抑郁样表型；然而，P2rx7 对海马体与抑郁相关的结构变化的影响尚未阐明。
使用习得性无助抑郁小鼠模型，研究 P2rx7 基因缺失对抑郁样行为和齿状回树突棘突触密度的影响。
我们证明，在野生型动物中，无法逃避的足部电击会导致习得性无助行为，表现为对随后可逃避的足部电击的潜伏期和逃避失败次数增加。这种行为伴随着 P2rx7 编码 mRNA 的下调和电子显微镜体视学测定的齿状回树突棘突触密度降低。此外，在这些条件下，还观察到突触小体蛋白而不是 PSD95 和 NR2B/GluN2B 蛋白水平的降低。而 P2rx7 的缺失表现为逃避缺陷，这些动物中没有观察到习得性无助行为。同样，在 P2rx7 缺失的动物中，无法逃避的足部电击不会导致树突棘突触数量和突触小体蛋白水平降低。
我们的发现表明，在抑郁的习得性无助模型中，内源性激活的 P2rx7s 和 P2rx7 缺失小鼠的树突棘突触可塑性降低可能解释了这些动物对重复应激刺激的抵抗力。
