NEIL3 shapes hippocampal network dynamics and fear memory through modulation of PV+ interneurons.

IF 6.1 2区 医学 Q1 NEUROSCIENCES
Marion Silvana Fernandez-Berrocal, Dagny Sanden Døskeland, Vidar Langseth Saasen, Anna Maria Bugaj, Nicolas Kunath, Mina Heggedal, Mouzuna Munir, Robert Christoffer Marthinsen, Milan Dekovic Ekeli, Katja Scheffler, Magnar Bjørås, Jing Ye
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Abstract

The dynamic balance between excitatory and inhibitory (E/I) signaling is critical for hippocampal network function and memory processing. Here, we uncover a novel role for the DNA glycosylase Endonuclease VIII-like 3 (NEIL3) in maintaining this E/I balance through its impact on parvalbumin-positive (PV⁺) GABAergic interneurons. NEIL3 deficiency leads to a selective reduction in PV⁺ interneurons and impaired perineuronal net (PNN) integrity, likely contributing to further PV⁺ neuron dysfunction. These changes result in altered hippocampal oscillatory dynamics, including increased beta and low gamma power, and reduced high gamma and ripple activity. These network alterations are accompanied by distinct effects on fear memory, as demonstrated using contextual and trace fear conditioning paradigms. NEIL3-deficient mice exhibited enhanced extinction of contextual fear memory but impaired extinction of trace fear memory. These findings suggest that the integrity of inhibitory networks plays differential roles in the spatial versus temporal aspects of fear memory extinction. Transcriptomic analysis further reveals dysregulation of genes involved in glutamatergic and GABAergic signaling. Among these, Gabra2 showed a marked downregulation, potentially driven by changes in promoter DNA methylation. This work identifies NEIL3 as an important regulator of the hippocampal inhibitory network, linking PV+ interneuron integrity and oscillatory coordination to distinct memory outcomes, and offers potential mechanistic insight into processes that may contribute to cognitive deficits in disorders characterized by E/I imbalance.

NEIL3通过调节PV+中间神经元影响海马网络动力学和恐惧记忆。
兴奋性和抑制性(E/I)信号的动态平衡对海马网络功能和记忆加工至关重要。在这里,我们揭示了DNA糖基酶内切酶VIII-like 3 (NEIL3)通过影响小蛋白阳性(PV +) gaba能中间神经元来维持这种E/I平衡的新作用。NEIL3缺乏导致PV +中间神经元的选择性减少和周围神经元网络(PNN)完整性受损,可能导致PV +神经元进一步功能障碍。这些变化导致海马振荡动力学改变,包括增加β和低伽马功率,减少高伽马和纹波活动。这些网络变化伴随着对恐惧记忆的明显影响,正如使用情境和追踪恐惧条件反射范例所证明的那样。neil3缺失小鼠情境恐惧记忆消退增强,痕迹恐惧记忆消退减弱。这些发现表明,抑制网络的完整性在恐惧记忆消退的空间和时间方面起着不同的作用。转录组学分析进一步揭示了参与谷氨酸能和gaba能信号传导的基因失调。其中,Gabra2表现出明显的下调,可能是由启动子DNA甲基化的变化驱动的。本研究确定NEIL3是海马抑制网络的重要调节因子,将PV+中间神经元的完整性和振荡协调与不同的记忆结果联系起来,并为可能导致以E/I失衡为特征的疾病的认知缺陷的过程提供了潜在的机制见解。
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来源期刊
Progress in Neurobiology
Progress in Neurobiology 医学-神经科学
CiteScore
12.80
自引率
1.50%
发文量
107
审稿时长
33 days
期刊介绍: Progress in Neurobiology is an international journal that publishes groundbreaking original research, comprehensive review articles and opinion pieces written by leading researchers. The journal welcomes contributions from the broad field of neuroscience that apply neurophysiological, biochemical, pharmacological, molecular biological, anatomical, computational and behavioral analyses to problems of molecular, cellular, developmental, systems, and clinical neuroscience.
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