Gebril Hoda, Wahba Amir, Zhou Xiaofeng, Lai Tho, Alharfoush Enmar, DiCicco-Bloom Emanuel, Boison Detlev
Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854.
Department of Neuroscience and Cell Biology/Pediatrics, Rutgers Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854.
eNeuro. 2021 Jun 2;8(3). doi: 10.1523/ENEURO.0011-21.2021. Print 2021 May-Jun.
Adenosine acts as a neuromodulator and metabolic regulator of the brain through receptor dependent and independent mechanisms. In the brain, adenosine is tightly controlled through its metabolic enzyme adenosine kinase (ADK), which exists in a cytoplasmic (ADK-S) and nuclear (ADK-L) isoform. We recently discovered that ADK-L contributes to adult hippocampal neurogenesis regulation. Although the cerebellum (CB) is a highly plastic brain area with a delayed developmental trajectory, little is known about the role of ADK. Here, we investigated the developmental profile of ADK expression in C57BL/6 mice CB and assessed its role in developmental and proliferative processes. We found high levels of ADK-L during cerebellar development, which was maintained into adulthood. This pattern contrasts with that of the cerebrum, in which ADK-L expression is gradually downregulated postnatally and largely restricted to astrocytes in adulthood. Supporting a functional role in cell proliferation, we found that the ADK inhibitor 5-iodotubericine (5-ITU) reduced DNA synthesis of granular neuron precursors in a concentration-dependent manner In the developing CB, immunohistochemical studies indicated ADK-L is expressed in immature Purkinje cells and granular neuron precursors, whereas in adulthood, ADK is absent from Purkinje cells, but widely expressed in mature granule neurons and their molecular layer (ML) processes. Furthermore, ADK-L is expressed in developing and mature Bergmann glia in the Purkinje cell layer, and in astrocytes in major cerebellar cortical layers. Together, our data demonstrate an association between neuronal ADK expression and developmental processes of the CB, which supports a functional role of ADK-L in the plasticity of the CB.
腺苷通过受体依赖性和非依赖性机制发挥大脑神经调节剂和代谢调节剂的作用。在大脑中,腺苷通过其代谢酶腺苷激酶(ADK)受到严格调控,腺苷激酶存在细胞质(ADK-S)和细胞核(ADK-L)两种同工型。我们最近发现ADK-L有助于成年海马体神经发生的调节。尽管小脑(CB)是一个具有延迟发育轨迹的高度可塑性脑区,但关于ADK的作用却知之甚少。在这里,我们研究了C57BL/6小鼠小脑ADK表达的发育情况,并评估了其在发育和增殖过程中的作用。我们发现小脑发育过程中ADK-L水平很高,并持续到成年期。这种模式与大脑不同,在大脑中,ADK-L的表达在出生后逐渐下调,成年后主要局限于星形胶质细胞。为了支持其在细胞增殖中的功能作用,我们发现ADK抑制剂5-碘结核菌素(5-ITU)以浓度依赖性方式降低颗粒神经元前体细胞的DNA合成。在发育中的小脑中,免疫组织化学研究表明ADK-L在未成熟的浦肯野细胞和颗粒神经元前体细胞中表达,而在成年期,浦肯野细胞中不存在ADK,但在成熟的颗粒神经元及其分子层(ML)突起中广泛表达。此外,ADK-L在浦肯野细胞层发育中和成熟的伯格曼胶质细胞中表达,以及在小脑主要皮质层的星形胶质细胞中表达。总之,我们的数据表明神经元ADK表达与小脑发育过程之间存在关联,这支持了ADK-L在小脑可塑性中的功能作用。
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