Neonatal inflammation increases hippocampal KCC2 expression through methylation-mediated TGF-β1 downregulation leading to impaired hippocampal cognitive function and synaptic plasticity in adult mice
Abstract The mechanisms by which neonatal inflammation leads to cognitive deficits in adulthood remain poorly understood. Inhibitory GABAergic synaptic transmission plays a vital role in controlling learning, memory and synaptic plasticity. Since early-life inflammation has been reported to adversel...
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| Format: | Article |
| Language: | English |
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BMC
2023-01-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-023-02697-x |
| _version_ | 1811175774956290048 |
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| author | Jing Rong Yang Yang Min Liang Haiquan Zhong Yingchun Li Yichao Zhu Sha Sha Lei Chen Rong Zhou |
| author_facet | Jing Rong Yang Yang Min Liang Haiquan Zhong Yingchun Li Yichao Zhu Sha Sha Lei Chen Rong Zhou |
| author_sort | Jing Rong |
| collection | DOAJ |
| description | Abstract The mechanisms by which neonatal inflammation leads to cognitive deficits in adulthood remain poorly understood. Inhibitory GABAergic synaptic transmission plays a vital role in controlling learning, memory and synaptic plasticity. Since early-life inflammation has been reported to adversely affect the GABAergic synaptic transmission, the aim of this study was to investigate whether and how neonatal inflammation affects GABAergic synaptic transmission resulting in cognitive impairment. Neonatal mice received a daily subcutaneous injection of lipopolysaccharide (LPS, 50 μg/kg) or saline on postnatal days 3–5. It was found that blocking GABAergic synaptic transmission reversed the deficit in hippocampus-dependent memory or the induction failure of long-term potentiation in the dorsal CA1 in adult LPS mice. An increase of mIPSCs amplitude was further detected in adult LPS mice indicative of postsynaptic potentiation of GABAergic transmission. Additionally, neonatal LPS resulted in the increased expression and function of K+–Cl−-cotransporter 2 (KCC2) and the decreased expression of transforming growth factor-beta 1 (TGF-β1) in the dorsal CA1 during adulthood. The local TGF-β1 overexpression improved KCC2 expression and function, synaptic plasticity and memory of adult LPS mice. Adult LPS mice show hypermethylation of TGFb1 promoter and negatively correlate with reduced TGF-β1 transcripts. 5-Aza-deoxycytidine restored the changes in TGFb1 promoter methylation and TGF-β1 expression. Altogether, the results suggest that hypermethylation-induced reduction of TGF-β1 leads to enhanced GABAergic synaptic inhibition through increased KCC2 expression, which is a underlying mechanism of neonatal inflammation-induced hippocampus-dependent memory impairment in adult mice. |
| first_indexed | 2024-04-10T19:42:24Z |
| format | Article |
| id | doaj.art-cdc895b858904e009e2de84585961e0e |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-10T19:42:24Z |
| publishDate | 2023-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-cdc895b858904e009e2de84585961e0e2023-01-29T12:17:58ZengBMCJournal of Neuroinflammation1742-20942023-01-0120111810.1186/s12974-023-02697-xNeonatal inflammation increases hippocampal KCC2 expression through methylation-mediated TGF-β1 downregulation leading to impaired hippocampal cognitive function and synaptic plasticity in adult miceJing Rong0Yang Yang1Min Liang2Haiquan Zhong3Yingchun Li4Yichao Zhu5Sha Sha6Lei Chen7Rong Zhou8Department of Physiology, Nanjing Medical UniversityDepartment of Physiology, Nanjing Medical UniversityDepartment of Physiology, Nanjing Medical UniversityDepartment of Physiology, Nanjing Medical UniversityDepartment of Physiology, Nanjing Medical UniversityDepartment of Physiology, Nanjing Medical UniversityDepartment of Physiology, Nanjing Medical UniversityDepartment of Physiology, Nanjing Medical UniversityDepartment of Physiology, Nanjing Medical UniversityAbstract The mechanisms by which neonatal inflammation leads to cognitive deficits in adulthood remain poorly understood. Inhibitory GABAergic synaptic transmission plays a vital role in controlling learning, memory and synaptic plasticity. Since early-life inflammation has been reported to adversely affect the GABAergic synaptic transmission, the aim of this study was to investigate whether and how neonatal inflammation affects GABAergic synaptic transmission resulting in cognitive impairment. Neonatal mice received a daily subcutaneous injection of lipopolysaccharide (LPS, 50 μg/kg) or saline on postnatal days 3–5. It was found that blocking GABAergic synaptic transmission reversed the deficit in hippocampus-dependent memory or the induction failure of long-term potentiation in the dorsal CA1 in adult LPS mice. An increase of mIPSCs amplitude was further detected in adult LPS mice indicative of postsynaptic potentiation of GABAergic transmission. Additionally, neonatal LPS resulted in the increased expression and function of K+–Cl−-cotransporter 2 (KCC2) and the decreased expression of transforming growth factor-beta 1 (TGF-β1) in the dorsal CA1 during adulthood. The local TGF-β1 overexpression improved KCC2 expression and function, synaptic plasticity and memory of adult LPS mice. Adult LPS mice show hypermethylation of TGFb1 promoter and negatively correlate with reduced TGF-β1 transcripts. 5-Aza-deoxycytidine restored the changes in TGFb1 promoter methylation and TGF-β1 expression. Altogether, the results suggest that hypermethylation-induced reduction of TGF-β1 leads to enhanced GABAergic synaptic inhibition through increased KCC2 expression, which is a underlying mechanism of neonatal inflammation-induced hippocampus-dependent memory impairment in adult mice.https://doi.org/10.1186/s12974-023-02697-xNeonatal inflammationMemoryGABAergic synaptic transmissionCytokinesMethylation |
| spellingShingle | Jing Rong Yang Yang Min Liang Haiquan Zhong Yingchun Li Yichao Zhu Sha Sha Lei Chen Rong Zhou Neonatal inflammation increases hippocampal KCC2 expression through methylation-mediated TGF-β1 downregulation leading to impaired hippocampal cognitive function and synaptic plasticity in adult mice Journal of Neuroinflammation Neonatal inflammation Memory GABAergic synaptic transmission Cytokines Methylation |
| title | Neonatal inflammation increases hippocampal KCC2 expression through methylation-mediated TGF-β1 downregulation leading to impaired hippocampal cognitive function and synaptic plasticity in adult mice |
| title_full | Neonatal inflammation increases hippocampal KCC2 expression through methylation-mediated TGF-β1 downregulation leading to impaired hippocampal cognitive function and synaptic plasticity in adult mice |
| title_fullStr | Neonatal inflammation increases hippocampal KCC2 expression through methylation-mediated TGF-β1 downregulation leading to impaired hippocampal cognitive function and synaptic plasticity in adult mice |
| title_full_unstemmed | Neonatal inflammation increases hippocampal KCC2 expression through methylation-mediated TGF-β1 downregulation leading to impaired hippocampal cognitive function and synaptic plasticity in adult mice |
| title_short | Neonatal inflammation increases hippocampal KCC2 expression through methylation-mediated TGF-β1 downregulation leading to impaired hippocampal cognitive function and synaptic plasticity in adult mice |
| title_sort | neonatal inflammation increases hippocampal kcc2 expression through methylation mediated tgf β1 downregulation leading to impaired hippocampal cognitive function and synaptic plasticity in adult mice |
| topic | Neonatal inflammation Memory GABAergic synaptic transmission Cytokines Methylation |
| url | https://doi.org/10.1186/s12974-023-02697-x |
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