Cell-autonomous GABAARs are essential for NMDAR-mediated synaptic transmission, LTP, and spatial memory.

IF 6.2 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

EMBO Reports Pub Date : 2025-09-01 Epub Date: 2025-07-30 DOI:10.1038/s44319-025-00538-x

Jing-Jing Duan, Bin Jiang, Wei Yin, Yuan Lin, Guang-Mei Yan, Wei Lu

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Abstract

GABA_A receptors (GABA_ARs) mediate most synaptic inhibition in the brain, but their cell-autonomous role in regulating glutamatergic transmission remains poorly understood. By targeting GABA_AR β1-3 subunit alleles (GABRB1-3) at once, we genetically eliminated GABA_ARs in individual hippocampal CA1 pyramidal neurons. We find that single-cell silencing of GABAergic transmission does not alter AMPAR-mediated synaptic transmission, but leads to a reduction in NMDAR-mediated synaptic transmission, loss of long-term potentiation (LTP), and impaired spatial memory. Genetic rescue experiments reveal that NMDAR-mediated whole-cell currents and synaptic transmission depend on specific GABA_AR subtypes and are tightly regulated by neuronal excitability. Pharmacologically restoring NMDAR function in β123-CRISPR mice rescues both LTP and spatial memory deficits induced by the loss of GABA_ARs in CA1 neurons. Our data uncover a previously unknown regulation of synaptic NMDAR functions by GABA_ARs at the single-cell level and provide insight into excitation and inhibition balance between GABA_ARs and NMDARs in the brain.

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细胞自主GABAARs对nmdar介导的突触传递、LTP和空间记忆至关重要。

GABAA受体（GABAARs）介导大脑中大多数突触抑制，但其在调节谷氨酸能传递中的细胞自主作用仍然知之甚少。通过一次性靶向GABAAR β1-3亚基等位基因（GABRB1-3），我们从基因上消除了个体海马CA1锥体神经元中的GABAARs。我们发现单细胞沉默gaba能传递不会改变ampar介导的突触传递，但会导致nmda介导的突触传递减少、长期增强（LTP）丧失和空间记忆受损。遗传拯救实验表明，nmdar介导的全细胞电流和突触传递依赖于特定的GABAAR亚型，并受到神经元兴奋性的严格调节。从药理学上恢复β123-CRISPR小鼠的NMDAR功能可以修复CA1神经元中GABAARs缺失引起的LTP和空间记忆缺陷。我们的数据揭示了以前未知的GABAARs在单细胞水平上对突触NMDAR功能的调节，并为大脑中GABAARs和NMDARs之间的兴奋和抑制平衡提供了见解。

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

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

期刊介绍： EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry.