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Topoisomerase 3? knockout mice show transcriptional and behavioural impairments associated with neurogenesis and synaptic plasticity.

ABSTRACT: Topoisomerase 3? (Top3?) is the only dual-activity topoisomerase in animals that can change topology for both DNA and RNA, and facilitate transcription on DNA and translation on mRNAs. Top3? mutations have been linked to schizophrenia, autism, epilepsy, and cognitive impairment. Here we show that Top3? knockout mice exhibit behavioural phenotypes related to psychiatric disorders and cognitive impairment. The mice also display impairments in hippocampal neurogenesis and synaptic plasticity. Notably, the brains of the mutant mice exhibit impaired global neuronal activity-dependent transcription in response to fear conditioning stress, and the affected genes include many with known neuronal functions. Our data suggest that Top3? is essential for normal brain function, and that defective neuronal activity-dependent transcription may be a mechanism by which Top3? deletion causes cognitive impairment and psychiatric disorders.

SUBMITTER: Joo Y

PROVIDER: S-EPMC7305123 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Topoisomerase 3β knockout mice show transcriptional and behavioural impairments associated with neurogenesis and synaptic plasticity.

Joo Yuyoung Y Xue Yutong Y Wang Yue Y McDevitt Ross A RA Sah Nirnath N Bossi Simone S Su Shuaikun S Lee Seung Kyu SK Peng Wei W Xie Aoji A Zhang Yongqing Y Ding Yi Y Ku Wai Lim WL Ghosh Soumita S Fishbein Kenneth K Shen Weiping W Spencer Richard R Becker Kevin K Zhao Keji K Mattson Mark P MP van Praag Henriette H Sharov Alexei A Wang Weidong W

Nature communications 20200619 1

Topoisomerase 3β (Top3β) is the only dual-activity topoisomerase in animals that can change topology for both DNA and RNA, and facilitate transcription on DNA and translation on mRNAs. Top3β mutations have been linked to schizophrenia, autism, epilepsy, and cognitive impairment. Here we show that Top3β knockout mice exhibit behavioural phenotypes related to psychiatric disorders and cognitive impairment. The mice also display impairments in hippocampal neurogenesis and synaptic plasticity. Notab ...[more]

PMID: 32561719

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Project description:Neuroinflammation plays an important role in the onset and progression of neurodegenerative diseases such as Alzheimer's disease. Lipopolysaccharide (LPS, endotoxin) levels are higher in the brains of Alzheimer's disease patients and are associated with neuroinflammation and cognitive decline, while neural cholinergic signaling controls inflammation. This study aimed to examine the efficacy of galantamine, a clinically approved cholinergic agent, in alleviating LPS-induced neuroinflammation and cognitive decline as well as the associated mechanism.Mice were treated with galantamine (4 mg/kg, intraperitoneal injection) for 14 days prior to LPS exposure (intracerebroventricular injection). Cognitive tests were performed, including the Morris water maze and step-through tests. mRNA expression of the microglial marker (CD11b), astrocytic marker (GFAP), and pro-inflammatory cytokines (IL-1?, IL-6, and TNF-?) were examined in the hippocampus by quantitative RT-PCR. The inflammatory signaling molecule, nuclear factor-kappa B (NF-?B p65), and synapse-associated proteins (synaptophysin, SYN, and postsynaptic density protein 95, PSD-95) were examined in the hippocampus by western blotting. Furthermore, NF-?B p65 levels in microglial cells and hippocampal neurons were examined in response to LPS and galantamine.Galantamine treatment prevented LPS-induced deficits in spatial learning and memory as well as memory acquisition of the passive avoidance response. Galantamine decreased the expression of microglia and astrocyte markers (CD11b and GFAP), pro-inflammatory cytokines (IL-1?, IL-6, and TNF-?), and NF-?B p65 in the hippocampus of LPS-exposed mice. Furthermore, galantamine ameliorated LPS-induced loss of synapse-associated proteins (SYN and PSD-95) in the hippocampus. In the in vitro study, LPS increased NF-?B p65 levels in microglia (BV-2 cells); the supernatant of LPS-stimulated microglia (Mi-sup), but not LPS, decreased the viability of hippocampal neuronal cells (HT-22 cells) and increased NF-?B p65 levels as well as expression of pro-inflammatory cytokines (IL-1?, IL-6) in HT-22 cells. Importantly, galantamine reduced the inflammatory response not only in the BV-2 microglia cell line, but also in the HT-22 hippocampal neuronal cell line.These findings indicate that galantamine could be a promising treatment to improve endotoxin-induced cognitive decline and neuroinflammation in neurodegenerative diseases.

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Topoisomerase 3? knockout mice show transcriptional and behavioural impairments associated with neurogenesis and synaptic plasticity.

Publications

Topoisomerase 3β knockout mice show transcriptional and behavioural impairments associated with neurogenesis and synaptic plasticity.

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