The promise of cyclic AMP modulation to restore cognitive function in neurodevelopmental disorders

IF 4.8 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology Pub Date : 2025-02-01 DOI:10.1016/j.conb.2024.102966

Aniket Bhattacharya , Luka Turkalj , M. Chiara Manzini

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Abstract

Cyclic AMP (cAMP) is a key regulator of synaptic function and is dysregulated in both neurodevelopmental (NDD) and neurodegenerative disorders. Due to the ease of diffusion and promiscuity of downstream effectors, cAMP signaling is restricted within spatiotemporal domains to localize activation. Among the best-studied mechanisms is the feedback inhibition of cAMP-dependent protein kinase (PKA) activity by phosphodiesterases 4 (PDE4s) at synapses controlling neuronal plasticity, which is largely regulated by PDE4D. In fact, genetic variants in genes for multiple PKA subunits and PDE4D lead to NDDs. Here, we discuss the rationale for choosing PDE4D as a candidate for the design of selective allosteric inhibitors and the recent advances in clinical trials. These new compounds improve cognitive function in preclinical animal models due to improved selectivity and more physiological inhibition of the active enzyme. We also discuss opportunities for better understanding of PDE4D function in general, and for the development of next-generation inhibitors.

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循环AMP调节恢复神经发育障碍患者认知功能的前景。

环AMP （cAMP）是突触功能的关键调节因子，在神经发育（NDD）和神经退行性疾病中都存在失调。由于下游效应物易于扩散和混杂，cAMP信号被限制在时空域中以局部激活。其中研究最多的机制是磷酸二酯酶4 （PDE4s）在控制神经元可塑性的突触上对camp依赖性蛋白激酶（PKA）活性的反馈抑制，这在很大程度上是由PDE4D调节的。事实上，多个PKA亚基和PDE4D基因的遗传变异会导致ndd。在这里，我们讨论了选择PDE4D作为设计选择性变构抑制剂的基本原理以及临床试验的最新进展。这些新化合物在临床前动物模型中由于提高了选择性和更多的生理抑制活性酶而改善了认知功能。我们还讨论了更好地了解PDE4D功能的机会，以及开发下一代抑制剂的机会。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Current Opinion in Neurobiology 医学-神经科学

CiteScore

11.10

自引率

1.80%

发文量

130

审稿时长

4-8 weeks

期刊介绍： Current Opinion in Neurobiology publishes short annotated reviews by leading experts on recent developments in the field of neurobiology. These experts write short reviews describing recent discoveries in this field (in the past 2-5 years), as well as highlighting select individual papers of particular significance. The journal is thus an important resource allowing researchers and educators to quickly gain an overview and rich understanding of complex and current issues in the field of Neurobiology. The journal takes a unique and valuable approach in focusing each special issue around a topic of scientific and/or societal interest, and then bringing together leading international experts studying that topic, embracing diverse methodologies and perspectives. Journal Content: The journal consists of 6 issues per year, covering 8 recurring topics every other year in the following categories: -Neurobiology of Disease- Neurobiology of Behavior- Cellular Neuroscience- Systems Neuroscience- Developmental Neuroscience- Neurobiology of Learning and Plasticity- Molecular Neuroscience- Computational Neuroscience