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 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.

Praeruptorin C alleviates cognitive impairment in type 2 diabetic mice through restoring PI3K/AKT/GSK3β pathway

“…LTP is the most widely used paradigm to study molecular and cellular events underlying synaptic transmission and is considered a putative mechanism for learning and memory (Bliss & Collingridge, 1993). Impaired LTP at the hippocampal synapses is a potential neurobiological mechanism underlying cognitive impairment, as learning and memory deficits are commonly observed in animals with impaired LTP (Rong et al, 2023; Zhu et al, 2022). Several natural products and derived compounds have been reported to alleviate cognitive impairment by repairing impaired LTP (Choi et al, 2023; Park et al, 2021; Wang et al, 2023).…”

“…(d) Root mean squared deviation (RMSD) and (e) root mean squared fluctuation (RMSF) line plots of the PI3K-Pra-C complex during 200 ps stimulation.putative mechanism for learning and memory(Bliss & Collingridge, 1993). Impaired LTP at the hippocampal synapses is a potential neurobiological mechanism underlying cognitive impairment, as learning and memory deficits are commonly observed in animals with impaired LTP(Rong et al, 2023;Zhu et al, 2022). Several natural products and derived compounds have been reported to alleviate F I G U R E 6 Praeruptorin C (Pra-C) restored PI3K/AKT/GSK3β signaling pathway in the hippocampus.…”

Bidirectional Regulation of GABAA Reversal Potential in the Adult Brain: Physiological and Pathological Implications

“…However, recent investigations have shown that the opposite regulation can also be detrimental and that excessive GABAA-mediated inhibition due to hypernegative current reversal potential represents another potential mechanism of pathology. For example, adult mice that were exposed to neonatal inflammation (using an LPS injection) show cognitive impairments associated with hypernegative GABAA reversal potential and increased KCC2 activity in the hippocampus [79]. Interestingly, these authors showed a complex TGF-β1-dependent regulation, suggesting the alteration is not simply due to an overdrive of the normal developmental KCC2 upregulation.…”