Critical Role of TLR4 on the Microglia Activation Induced by Maternal LPS Exposure Leading to ASD-Like Behavior of Offspring

Objective: To investigate the role of TLR4 on the microglia activation in the pre-frontal cortex, which leads to autism-like behavior of the offspring induced by maternal lipopolysaccharide (LPS) exposure.Methods: Pregnant TLR4−/− (knockout, KO) and WT (wild type, WT) dams were intraperitoneally injected with LPS or PBS, respectively. The levels of TNFα, IL-1β, and IL-6 in the maternal serum and fetal brain were assessed with ELISA following LPS exposure. The gestation period, litter size and weight of the offspring were evaluated. Three-chamber sociability test, open field test and olfactory habituation/dishabituation test were used to assess the offspring's autism-like behavior at 7 weeks of age. Western blotting was performed to examine the levels of TLR4, Phospho-NFκB p65, IKKα, IBA-1, iNOS, Arg-1, C3, CR3A, NMDAR2A, and Syn-1 expression in the pre-frontal cortex. The morphological changes in the microglia, the distribution and expression of TLR4 were observed by immunofluorescence staining. Golgi-Cox staining was conducted to evaluate the dendritic length and spine density of the neurons in 2-week-old offspring.Results: Maternal LPS stimulation increased serum TNFα and IL-6, as well as fetal brain TNFα in the WT mice. The litter size and the weight of the WT offspring were significantly reduced following maternal LPS treatment. LPS-treated WT offspring had lower social and self-exploration behavior, and greater anxiety and repetitive behaviors. The protein expression levels of TLR4 signaling pathways, including TLR4, Phospho-NFκB p65, IKKα, and IBA-1, iNOS expression were increased in the LPS-treated WT offspring, whereas Arg-1 was decreased. Maternal LPS treatment resulted in the significant reduction in the levels of the synaptic pruning-related proteins, C3 and CR3A. Moreover, the neuronal dendritic length and spine density, as well as the expression levels of the synaptic plasticity-related proteins, NMDAR2A and Syn-1 were reduced in the WT offspring; however, gestational LPS exposure had no effect on the TLR4−/− offspring.Conclusion: Activation of TLR4 signaling pathway following maternal LPS exposure induced the abnormal activation of microglia, which in turn was involved in excessive synaptic pruning to decrease synaptic plasticity in the offspring. This may be one of the reasons for the autism-like behavior in the offspring mice.

Download Full-text

Locus Coeruleus and Dopamine-Dependent Memory Consolidation

Neural Plasticity ◽

10.1155/2017/8602690 ◽

2017 ◽

Vol 2017 ◽

pp. 1-15 ◽

Cited By ~ 17

Author(s):

Miwako Yamasaki ◽

Tomonori Takeuchi

Keyword(s):

Synaptic Plasticity ◽

Locus Coeruleus ◽

Memory Consolidation ◽

Molecular Mechanisms ◽

Memory Enhancement ◽

Long Time ◽

Related Proteins ◽

Anatomical Evidence ◽

Environmental Novelty

Most everyday memories including many episodic-like memories that we may form automatically in the hippocampus (HPC) are forgotten, while some of them are retained for a long time by a memory stabilization process, called initial memory consolidation. Specifically, the retention of everyday memory is enhanced, in humans and animals, when something novel happens shortly before or after the time of encoding. Converging evidence has indicated that dopamine (DA) signaling via D1/D5receptors in HPC is required for persistence of synaptic plasticity and memory, thereby playing an important role in the novelty-associated memory enhancement. In this review paper, we aim to provide an overview of the key findings related to D1/D5receptor-dependent persistence of synaptic plasticity and memory in HPC, especially focusing on the emerging evidence for a role of the locus coeruleus (LC) in DA-dependent memory consolidation. We then refer to candidate brain areas and circuits that might be responsible for detection and transmission of the environmental novelty signal and molecular and anatomical evidence for the LC-DA system. We also discuss molecular mechanisms that might mediate the environmental novelty-associated memory enhancement, including plasticity-related proteins that are involved in initial memory consolidation processes in HPC.

Download Full-text

Hidden prenatal malnutrition in the rat: role of β1-adrenoceptors on synaptic plasticity in the frontal cortex

Journal of Neurochemistry ◽

10.1111/j.1471-4159.2011.07429.x ◽

2011 ◽

Vol 119 (2) ◽

pp. 314-323 ◽

Cited By ~ 16

Author(s):

Osvaldo Flores ◽

Hernán Pérez ◽

Luis Valladares ◽

Carlos Morgan ◽

Arnaldo Gatica ◽

...

Keyword(s):

Synaptic Plasticity ◽

Frontal Cortex ◽

Prenatal Malnutrition

Download Full-text

Knockdown MiR-302b Alleviates LPS-Induced Injury by Targeting Smad3 in C28/I2 Chondrocytic Cells

Cellular Physiology and Biochemistry ◽

10.1159/000487165 ◽

2018 ◽

Vol 45 (2) ◽

pp. 733-743 ◽

Cited By ~ 9

Author(s):

Yueshu Wang ◽

Tao Yu ◽

Hui Jin ◽

Changfu Zhao ◽

Yang Wang

Keyword(s):

Cell Viability ◽

Signaling Pathway ◽

Mtor Signaling ◽

Chondrocyte Apoptosis ◽

Mtor Signaling Pathway ◽

Smad3 Expression ◽

Apoptosis And Inflammation ◽

Related Proteins ◽

Lps Treatment

Background/Aims: Osteoarthritis (OA) is one of the most common chronic degenerative diseases. Many studies have demonstrated the role of microRNAs (miRNAs) in OA; however, the role of miR-302b in OA remains elusive. The aim of this study was to identify the role of miR-302b in LPS-induced injury in chondrocytes. Methods: Human OA chondrocytes (C28/12 cell line) were transfected with miR-302b inhibitor and miR-302b mimic to investigate the effects of miR-302b expression on chondrocyte apoptosis and inflammation, and to identify the miR-302b target proteins. Results: LPS treatment of chondrocytes significantly reduced cell viability and increased apoptotic rate. LPS treatment also increased the expression of inflammatory cytokines compared to control. miR-302b was up-regulated in LPS-induced chondrocytes. miR-302b was either suppressed or overexpressed in LPS-induced chondrocytes by transient transfection. miR-302b mimic transfection accelerated the effects of LPS on cell viability, apoptosis and inflammation. Of contrast, miR-302b inhibition represented a reverse effect. Dual luciferase activity demonstrated that Smad3 is a direct target for miR-302b and its expression was negatively regulated by miR-302b. In addition, miR-302b inhibition suppressed inflammation in LPS treated chondrocytes by up-regulating Smad3 expression. Moreover, LPS induced down-regulation of Notch and mTOR signaling pathway-related protein expressions, and miR-302b inhibition increased the expressions of Notch and mTOR signaling pathway-related proteins. We further found that miR-302b negatively regulated Notch2 levels through direct targeting its 3’UTR. Conclusions: These results suggest that miR-302b suppression may function as a protector in suppressing the inflammation during the development and progression of OA by up-regulating the target Smad3 expression.

Download Full-text

The pharmacological perturbation of brain zinc impairs BDNF-related signalling and the cognitive performances of young mice

10.1101/267609 ◽

2018 ◽

Author(s):

Valerio Frazzini ◽

Alberto Granzotto ◽

Manuela Bomba ◽

Noemi Massetti ◽

Vanessa Castelli ◽

...

Keyword(s):

Synaptic Plasticity ◽

Brain Activity ◽

Long Term Memory ◽

Spine Density ◽

Short And Long Term ◽

Copper Chelator ◽

Related Proteins ◽

Metalloproteinase Activity

AbstractZinc (Zn2+) is a pleiotropic modulator of the neuronal and brain activity. The disruption of intraneuronal Zn2+levels triggers neurotoxic processes and affects neuronal functioning. In this study, we investigated how the pharmacological modulation of brain Zn2+affects synaptic plasticity and cognition in wild-type mice. To manipulate brain Zn2+levels, we employed the Zn2+(and copper) chelator 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol, CQ). CQ was administered for two weeks to 2.5-month-old (m.o.) mice, and effects studied on BDNF-related signalling, metalloproteinase activity as well as learning and memory performances. CQ treatment was found to negatively affect short- and long-term memory performances. The CQ-driven perturbation of brain Zn2+was found to reduce levels of BDNF, synaptic plasticity-related proteins and dendritic spine densityin vivo.Our study highlights the importance of choosing “when”, “where”, and “how much” in the modulation of brain Zn2+levels. Our findings confirm the importance of targeting Zn2+as a therapeutic approach against neurodegenerative conditions but, at the same time, underscore the potential drawbacks of reducing brain Zn2+availability upon the early stages of development.

Download Full-text

Neuron-Derived Estrogen—A Key Neuromodulator in Synaptic Function and Memory

International Journal of Molecular Sciences ◽

10.3390/ijms222413242 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13242

Author(s):

Darrell W. Brann ◽

Yujiao Lu ◽

Jing Wang ◽

Gangadhara R. Sareddy ◽

Uday P. Pratap ◽

...

Keyword(s):

Synaptic Plasticity ◽

Knockout Mice ◽

Long Term Potentiation ◽

Reference Memory ◽

Synaptic Function ◽

Synaptic Proteins ◽

Spine Density ◽

And Function ◽

The Brain

In addition to being a steroid hormone, 17β-estradiol (E2) is also a neurosteroid produced in neurons in various regions of the brain of many species, including humans. Neuron-derived E2 (NDE2) is synthesized from androgen precursors via the action of the biosynthetic enzyme aromatase, which is located at synapses and in presynaptic terminals in neurons in both the male and female brain. In this review, we discuss evidence supporting a key role for NDE2 as a neuromodulator that regulates synaptic plasticity and memory. Evidence supporting an important neuromodulatory role of NDE2 in the brain has come from studies using aromatase inhibitors, aromatase overexpression in neurons, global aromatase knockout mice, and the recent development of conditional forebrain neuron-specific knockout mice. Collectively, these studies demonstrate a key role of NDE2 in the regulation of synapse and spine density, efficacy of excitatory synaptic transmission and long-term potentiation, and regulation of hippocampal-dependent recognition memory, spatial reference memory, and contextual fear memory. NDE2 is suggested to achieve these effects through estrogen receptor-mediated regulation of rapid kinase signaling and CREB-BDNF signaling pathways, which regulate actin remodeling, as well as transcription, translation, and transport of synaptic proteins critical for synaptic plasticity and function.

Download Full-text