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AP2γ 控制成年海马神经发生,并调节认知,但不调节焦虑或抑郁样行为。

AP2γ controls adult hippocampal neurogenesis and modulates cognitive, but not anxiety or depressive-like behavior.

机构信息

Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.

Life and Health Sciences Research Institute (ICVS)/3B's-PT Government Associate Laboratory, Guimarães, Portugal.

出版信息

Mol Psychiatry. 2017 Dec;22(12):1725-1734. doi: 10.1038/mp.2016.169. Epub 2016 Oct 25.

Abstract

Hippocampal neurogenesis has been proposed to participate in a myriad of behavioral responses, both in basal states and in the context of neuropsychiatric disorders. Here, we identify activating protein 2γ (AP2γ, also known as Tcfap2c), originally described to regulate the generation of neurons in the developing cortex, as a modulator of adult hippocampal glutamatergic neurogenesis in mice. Specifically, AP2γ is present in a sub-population of hippocampal transient amplifying progenitors. There, it is found to act as a positive regulator of the cell fate determinants Tbr2 and NeuroD, promoting proliferation and differentiation of new glutamatergic granular neurons. Conditional ablation of AP2γ in the adult brain significantly reduced hippocampal neurogenesis and disrupted neural coherence between the ventral hippocampus and the medial prefrontal cortex. Furthermore, it resulted in the precipitation of multimodal cognitive deficits. This indicates that the sub-population of AP2γ-positive hippocampal progenitors may constitute an important cellular substrate for hippocampal-dependent cognitive functions. Concurrently, AP2γ deletion produced significant impairments in contextual memory and reversal learning. More so, in a water maze reference memory task a delay in the transition to cognitive strategies relying on hippocampal function integrity was observed. Interestingly, anxiety- and depressive-like behaviors were not significantly affected. Altogether, findings open new perspectives in understanding the role of specific sub-populations of newborn neurons in the (patho)physiology of neuropsychiatric disorders affecting hippocampal neuroplasticity and cognitive function in the adult brain.

摘要

海马体神经发生被认为参与了多种行为反应,无论是在基础状态下还是在神经精神疾病的背景下。在这里,我们确定激活蛋白 2γ(AP2γ,也称为 Tcfap2c),最初被描述为调节皮质发育中神经元的产生,是调节小鼠成年海马谷氨酸能神经发生的调节剂。具体来说,AP2γ存在于海马体短暂扩增祖细胞的一个亚群中。在那里,它被发现作为细胞命运决定因素 Tbr2 和 NeuroD 的正调节剂,促进新谷氨酸能颗粒神经元的增殖和分化。AP2γ 在成年大脑中的条件性缺失显著减少了海马体神经发生,并破坏了腹侧海马体和内侧前额叶皮层之间的神经一致性。此外,它导致了多种认知缺陷的加剧。这表明,AP2γ 阳性海马祖细胞的亚群可能构成海马体依赖认知功能的重要细胞基础。同时,AP2γ 的缺失导致了情景记忆和反转学习的显著损伤。更重要的是,在水迷宫参考记忆任务中,观察到依赖海马体功能完整性的认知策略的过渡延迟。有趣的是,焦虑和抑郁样行为没有受到显著影响。总的来说,这些发现为理解特定新生神经元亚群在影响成年大脑海马体神经可塑性和认知功能的神经精神疾病的(病理)生理学中的作用提供了新的视角。

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