The homeostatic effects of the RE-1 silencing transcription factor on cortical networks are altered under ictogenic conditions in the mouse

IF 5.6 2区 医学 Q1 PHYSIOLOGY Acta Physiologica Pub Date : 2024-04-12 DOI:10.1111/apha.14146
Carmela Vitale, Giulia Natali, Maria Sabina Cerullo, Thomas Floss, Caterina Michetti, Giorgio Grasselli, Fabio Benfenati
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Abstract

Aim

The Repressor Element-1 Silencing Transcription Factor (REST) is an epigenetic master regulator playing a crucial role in the nervous system. In early developmental stages, REST downregulation promotes neuronal differentiation and the acquisition of the neuronal phenotype. In addition, postnatal fluctuations in REST expression contribute to shaping neuronal networks and maintaining network homeostasis. Here we investigate the role of the early postnatal deletion of neuronal REST in the assembly and strength of excitatory and inhibitory synaptic connections.

Methods

We investigated excitatory and inhibitory synaptic transmission by patch-clamp recordings in acute neocortical slices in a conditional knockout mouse model (RestGTi) in which Rest was deleted by delivering PHP.eB adeno-associated viruses encoding CRE recombinase under the control of the human synapsin I promoter in the lateral ventricles of P0-P1 pups.

Results

We show that, under physiological conditions, Rest deletion increased the intrinsic excitability of principal cortical neurons in the primary visual cortex and the density and strength of excitatory synaptic connections impinging on them, without affecting inhibitory transmission. Conversely, in the presence of a pathological excitation/inhibition imbalance induced by pentylenetetrazol, Rest deletion prevented the increase in synaptic excitation and decreased seizure severity.

Conclusion

The data indicate that REST exerts distinct effects on the excitability of cortical circuits depending on whether it acts under physiological conditions or in the presence of pathologic network hyperexcitability. In the former case, REST preserves a correct excitatory/inhibitory balance in cortical circuits, while in the latter REST loses its homeostatic activity and may become pro-epileptogenic.

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RE-1沉默转录因子对小鼠大脑皮层网络的平衡作用在致病条件下发生改变
目的抑制元件-1沉默转录因子(REST)是一种表观遗传主调节因子,在神经系统中发挥着至关重要的作用。在早期发育阶段,REST 的下调会促进神经元的分化和神经元表型的获得。此外,出生后 REST 表达的波动有助于塑造神经元网络并维持网络的平衡。在此,我们研究了出生后早期神经元REST的缺失在兴奋性和抑制性突触连接的组装和强度中的作用。方法我们在一个条件性基因敲除小鼠模型(RestGTi)中通过递送PHP.EB腺相关病毒(PHP.EB adeno-associated virus)在急性新皮质切片中进行贴片钳记录,研究了兴奋性和抑制性突触传递。结果我们发现,在生理条件下,Rest 基因缺失会增加初级视皮层主要皮层神经元的固有兴奋性以及影响它们的兴奋性突触连接的密度和强度,而不影响抑制性传导。相反,在戊四唑诱导的病理性兴奋/抑制失衡的情况下,REST的缺失会阻止突触兴奋的增加,并降低癫痫发作的严重程度。在前一种情况下,REST 可保持大脑皮层回路中正确的兴奋/抑制平衡,而在后一种情况下,REST 会失去其平衡活性,并可能变得有利于致痫。
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来源期刊
Acta Physiologica
Acta Physiologica 医学-生理学
CiteScore
11.80
自引率
15.90%
发文量
182
审稿时长
4-8 weeks
期刊介绍: Acta Physiologica is an important forum for the publication of high quality original research in physiology and related areas by authors from all over the world. Acta Physiologica is a leading journal in human/translational physiology while promoting all aspects of the science of physiology. The journal publishes full length original articles on important new observations as well as reviews and commentaries.
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