Enhanced Cognition and Neurogenesis in miR-146b Deficient Mice

Chithanathan, Keerthana; Somelar, Kelli; Jürgenson, Monika; Žarkovskaja, Tamara; Periyasamy, Kapilraj; Liu, Yan; Magilnick, Nathaniel; Boldin, Mark; Rebane, Ana; Tian, Li; Zharkovsky, Alexander

doi:10.3390/cells11132002

Cited by 6 publications

(9 citation statements)

References 79 publications

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“…We have previously demonstrated that Mir146b-/- mice did not differ from WT animals with regard of body weight, locomotor activity, food and water consumption, hippocampal and total brain volumes at the age of 2-3 months ( 22 ). It is known that systemic administration of LPS in animals leads a behavioral state called “sickness behavior”, which is characterized by lethargy, decreased locomotor activity and appetite, depression-like behavior, and increased sensitivity to pain ( 39 ).…”

Section: Resultsmentioning

confidence: 99%

“…Another study showed that treatment of microglial cells with LPS led to increased expression of miR-146b but not miR-146a, while transfection of miR-146b into microglial cells significantly decreased LPS-induced microglial activation and downregulated IRAK1 ( 31 ). Intriguingly, we reported that constitutive miR-146b deficiency didn’t cause microglial activation or signs of neuroinflammation in the hippocampus of the mouse brain ( 22 ). However, knowledge on the regulation of neuroinflammation in the absence of miR-146b is still lacking.…”

Section: Introductionmentioning

confidence: 99%

“…In the central nervous system, miR-146a is abundantly expressed in microglial cells ( 22 , 23 ). Numerous lines of genetic evidence suggest that polymorphisms in miR-146a can influence its function and thereby contribute to susceptibility to several neurological diseases ( 24 , 25 ).…”

Section: Introductionmentioning

confidence: 99%

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Paradoxical attenuation of neuroinflammatory response upon LPS challenge in miR-146b deficient mice

et al. 2022

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The miR-146 family consists of two microRNAs (miRNAs), miR-146a and miR-146b (miR-146a/b), both of which are known to suppress immune responses in a variety of conditions. Here, we studied how constitutive deficiency of miR-146b (Mir146b-/-) affects lipopolysaccharide (LPS)-induced neuroinflammation in mice. Our experiments demonstrated that miR-146b deficiency results in the attenuation of LPS-induced neuroinflammation, as it was evidenced by the reduction of sickness behavior, a decrease in the inflammatory status of microglia, and the loss of morphological signs of microglial activation in the hippocampus. Gene expression analysis revealed that LPS-induced upregulation of hippocampal pro-inflammatory cytokines is attenuated in Mir146b-/- mice, compared to wild-type (WT) mice. In addition, reduced expression of the NF-κB nuclear protein p65, reduced miR-146 family target TLR4 expression and relatively stronger upregulation of miR-146a was found in Mir146b-/- mice as compared to WT mice upon LPS challenge. Compensatory upregulation of miR-146a can explain the attenuation of the LPS-induced neuroinflammation. This was supported by experiments conducted with miR-146a/b deficient mice (Mir146a/b-/-), which demonstrated that additional deletion of the miR-146a led to the restoration of LPS-induced sickness behavior and proinflammatory cytokines. Our experiments also showed that the observed upregulation of miR-146a in Mir146b-/- mice is due to the overexpression of a miR-146a transcription inducer, interferon regulatory factor 7 (Irf7). Altogether, our results show the existence of crosstalk between miR-146a and mir-146b in the regulation of LPS-induced neuroinflammation.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Paradoxical attenuation of neuroinflammatory response upon LPS challenge in miR-146b deficient mice

et al. 2022

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“…The miR-146 family consists of the two evolutionarily conserved miRNAs miR-146a and miR-146b (Williams et al 2008 ; Matsumoto et al 2016 ). Since they are expressed in neurons, miR-146a and miR-146b have a role in neuronal development and the control of inflammation in the nervous system (Nguyen et al 2018 ; Chithanathan et al 2022 ). According to one study, gene networks that miR-146a targets are connected to ASD and can be utilized to predict the type and severity of ASD expression in addition to just diagnosing the ASD presence (Nguyen et al 2018 ).…”

Section: Discussionmentioning

confidence: 99%

The role of microRNAs in the molecular link between circadian rhythm and autism spectrum disorder

Kim

Lee

2023

Animal Cells and Systems

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Circadian rhythm regulates physiological cycles of awareness and sleepiness. Melatonin production is primarily regulated by circadian regulation of gene expression and is involved in sleep homeostasis. If the circadian rhythm is abnormal, sleep disorders, such as insomnia and several other diseases, can occur. The term ‘autism spectrum disorder (ASD)’ is used to characterize people who exhibit a certain set of repetitive behaviors, severely constrained interests, social deficits, and/or sensory behaviors that start very early in life. Because many patients with ASD suffer from sleep disorders, sleep disorders and melatonin dysregulation are attracting attention for their potential roles in ASD. ASD is caused by abnormalities during the neurodevelopmental processes owing to various genetic or environmental factors. Recently, the role of microRNAs (miRNAs) in circadian rhythm and ASD have gained attraction. We hypothesized that the relationship between circadian rhythm and ASD could be explained by miRNAs that can regulate or be regulated by either or both. In this study, we introduced a possible molecular link between circadian rhythm and ASD. We performed a thorough literature review to understand their complexity.

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“…In astrocytes, the miR-181 family typically controls neuroinflammatory signaling, and it has been observed that the AD environment increases its expression [ 65 ]. Other than miR-181, numerous miRs, which are involved in AD pathology, including miR-146a [ 66 ], miR-146b [ 67 ], and miR-155 [ 68 ], were elevated in cortical astrocytes of mice following LPS treatment [ 69 ]. The frontal cortex–hippocampal circuitry is involved in learning and memory.…”

Section: The Role Of Astrocytic Micrornas In Multiple Pathways In Admentioning

confidence: 99%

Astrocytic MicroRNAs and Transcription Factors in Alzheimer’s Disease and Therapeutic Interventions

Nassar

Kodi

Satarker

et al. 2022

Cells

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Astrocytes are important for maintaining cholesterol metabolism, glutamate uptake, and neurotransmission. Indeed, inflammatory processes and neurodegeneration contribute to the altered morphology, gene expression, and function of astrocytes. Astrocytes, in collaboration with numerous microRNAs, regulate brain cholesterol levels as well as glutamatergic and inflammatory signaling, all of which contribute to general brain homeostasis. Neural electrical activity, synaptic plasticity processes, learning, and memory are dependent on the astrocyte–neuron crosstalk. Here, we review the involvement of astrocytic microRNAs that potentially regulate cholesterol metabolism, glutamate uptake, and inflammation in Alzheimer’s disease (AD). The interaction between astrocytic microRNAs and long non-coding RNA and transcription factors specific to astrocytes also contributes to the pathogenesis of AD. Thus, astrocytic microRNAs arise as a promising target, as AD conditions are a worldwide public health problem. This review examines novel therapeutic strategies to target astrocyte dysfunction in AD, such as lipid nanodiscs, engineered G protein-coupled receptors, extracellular vesicles, and nanoparticles.

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Enhanced Cognition and Neurogenesis in miR-146b Deficient Mice

Cited by 6 publications

References 79 publications

Paradoxical attenuation of neuroinflammatory response upon LPS challenge in miR-146b deficient mice

Paradoxical attenuation of neuroinflammatory response upon LPS challenge in miR-146b deficient mice

The role of microRNAs in the molecular link between circadian rhythm and autism spectrum disorder

Astrocytic MicroRNAs and Transcription Factors in Alzheimer’s Disease and Therapeutic Interventions

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