Distinct in vivo role of APPsα versus APPsβ for spine density, synaptic plasticity and cognition

2018 ◽  
Author(s):  
Max Richter
Keyword(s):  
Synaptic Plasticity ◽  
Spine Density

scholarly journals GluA1 Phosphorylation Alters Evoked Firing PatternIn Vivo

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Balázs Barkóczi ◽  
Gábor Juhász ◽  
Robert G. Averkin ◽  
Imre Vörös ◽  
Petra Vertes ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Spike Trains ◽  
Temporal Coding ◽  
Relative Contribution ◽  
Ampa Receptor Subunit ◽  
Ampa And Nmda Receptors ◽  
Characteristic Features ◽  
Evoked Activity

AMPA and NMDA receptors convey fast synaptic transmission in the CNS. Their relative contribution to synaptic output and phosphorylation state regulate synaptic plasticity. The AMPA receptor subunit GluA1 is central in synaptic plasticity. Phosphorylation of GluA1 regulates channel properties and trafficking. The firing rate averaged over several hundred ms is used to monitor cellular input. However, plasticity requires the timing of spiking within a few ms; therefore, it is important to understand how phosphorylation governs these events. Here, we investigate whether the GluA1 phosphorylation (p-GluA1) alters the spiking patterns of CA1 cellsin vivo. The antidepressant Tianeptine was used for inducing p-GluA1, which resulted in enhanced AMPA-evoked spiking. By comparing the spiking patterns of AMPA-evoked activity with matched firing rates, we show that the spike-trains after Tianeptine application show characteristic features, distinguishing from spike-trains triggered by strong AMPA stimulation. The interspike-interval distributions are different between the two groups, suggesting that neuronal output may differ when new inputs are activated compared to increasing the gain of previously activated receptors. Furthermore, we also show that NMDA evokes spiking with different patterns to AMPA spike-trains. These results support the role of the modulation of NMDAR/AMPAR ratio and p-GluA1 in plasticity and temporal coding.

scholarly journals Increased Human Wildtype Tau Attenuates Axonal Transport Deficits Caused by Loss of App in Mouse Models

2010 ◽  
Vol 4 ◽  
pp. MRI.S5237 ◽  
Author(s):  
Karen D.B. Smith ◽  
Erica Peethumnongsin ◽  
Han Lin ◽  
Hui Zheng ◽  
Robia G. Pautler
Keyword(s):  
Synaptic Plasticity ◽  
Axonal Transport ◽  
Mouse Models ◽  
Knockout Mice ◽  
Early Age ◽  
Axonal Elongation ◽  
Protein Tau ◽  
Manganese Enhanced Mri

Amyloid precursor protein (APP) is implicated in axonal elongation, synaptic plasticity, and axonal transport. However, the role of APP on axonal transport in conjunction with the microtubule associated protein tau continues to be debated. Here we measured in vivo axonal transport in APP knockout mice with Manganese Enhanced MRI (MEMRI) to determine whether APP is necessary for maintaining normal axonal transport. We also tested how overexpression and mutations of tau affect axonal transport in the presence or absence of APP. In vivo axonal transport reduced significantly in the absence of functional APP. Overexpression of human wildtype tau maintained normal axonal transport and resulted in a transient compensation of axonal transport deficits in the absence of APP. Mutant R406Wtau in combination with the absence of APP compounded axonal transport deficits and these deficits persisted with age. These results indicate that APP is necessary for axonal transport, and overexpression of human wildtype tau can compensate for the absence of APP at an early age.

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

2021 ◽  
Vol 9 ◽  
Author(s):  
Lu Xiao ◽  
Junyan Yan ◽  
Di Feng ◽  
Shasha Ye ◽  
Ting Yang ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Frontal Cortex ◽  
Litter Size ◽  
Fetal Brain ◽  
Spine Density ◽  
Dendritic Length ◽  
Related Proteins ◽  
Lps Treatment ◽  
Synaptic Pruning

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.

scholarly journals Contributions of Microglia to Structural Synaptic Plasticity

2013 ◽  
Vol 7 ◽  
pp. JEN.S11269 ◽  
Author(s):  
Kyung Ho Kim ◽  
Sung Min Son ◽  
Inhee Mook-Jung
Keyword(s):  
Synaptic Plasticity ◽  
Brain Cell ◽  
In Vivo Studies ◽  
Neural Function ◽  
Special Role ◽  
Neuronal Synapses ◽  
Total Brain ◽  
Synaptic Changes

Synaptic plasticity critically depends on reciprocal interactions between neurons and glia. Among glial cells, microglia represent approximately 10% of the total brain cell population serve as the brain's resident macrophage, and help to modulate neural activity. Because of their special role in the brain's immune response, microglia are involved in the pathological progression of neurodegenerative disorders such as Alzheimer's disease (AD). However, microglia also are surveyors of the brain's health and continuously contact dendritic spines to regulate structural synaptic changes. This review summarizes our current understanding of neuronal-microglial signals that affect neural function at the synapse. Here, we examine the role of microglia in neuronal synapses in pathological brains and specifically focus on in vivo studies using 2-photon microscopy. Furthermore, because the role of microglia in AD progression is controversial, we outline the interaction between neurons and microglia in pathological conditions such as AD.

scholarly journals Assessing the therapeutic potential of APPs⍺ in a tau transgenic mouse model of Alzheimers disease

2020 ◽  
Author(s):  
Charlotte Bold ◽  
Danny Baltissen ◽  
Susann Ludewig ◽  
Roman Spilger ◽  
Karl Rohr ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Mouse Model ◽  
Therapeutic Potential ◽  
Large Body ◽  
Transgenic Mouse Model ◽  
Spine Density ◽  
General Applicability ◽  
Plaque Deposition

A large body of evidence indicates a neuroprotective and neurotrophic function for APPs⍺ not only in vitro, but also when expressed by AAV vectors in vivo such as in APP/PS1 transgenic AD model mice with Aβ-induced pathology. Previously, we could show that APPs⍺ rescued deficits of APP/PS1 in synaptic plasticity and spine density and also reduced plaque deposition. Thus, it is crucial to test a more general applicability of APPs⍺ as a treatment for AD and to assess whether APPs⍺ is also beneficial in mice with tau-induced pathology.

scholarly journals Methylglyoxal modification of TrkB promotes synaptic plasticity and enhances resilience to chronic stress

2018 ◽  
Author(s):  
Ziyin Wu ◽  
Yingxue Fu ◽  
Yinfeng Yang ◽  
Chao Huang ◽  
Chunli Zheng ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Synaptic Plasticity ◽  
Chronic Stress ◽  
Low Dose ◽  
Anxiety And Depression ◽  
Antidepressant Effects ◽  
Subsequent Activation

AbstractThe endogenous metabolite methylglyoxal (MGO) has recently emerged as a potential mediator of psychiatric disorders, such as anxiety and depression, but its precise mechanism of action remains poorly understood. Here, we find that MGO concentrations are decreased in the prefrontal cortex and hippocampus in rats subjected to chronic stress, and low-dose MGO treatment remarkedly enhances resilience to stress and alleviates depression-like symptoms. This effect is achieved by MGO’s promotion on the synaptic plasticity in prefrontal cortex and hippocampus. Both in vitro and in vivo experiments show that MGO provokes the dimerization and autophosphorylation of TrkB and the subsequent activation of downstream Akt/CREB signaling, which leads to a rapid and sustained expression of brain-derived neurotrophic factor (BDNF). We further demonstrate that MGO directly binds to the extracellular domain of TrkB, but not its intracellular domain. In addition, we also identify a natural product luteolin and its derivative lutD as potent inhibitors of Glyoxalase 1 and validate their antidepressant effects in chronic stress rat models. The antidepressant role of endogenous MGO provides a new basis for the understanding and therapeutic intervention design for stress-associated mental disorders.

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

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.

scholarly journals Distinct in vivo roles of secreted APP ectodomain variants APP sα and APP sβ in regulation of spine density, synaptic plasticity, and cognition

2018 ◽  
Vol 37 (11) ◽  
Author(s):  
Max C Richter ◽  
Susann Ludewig ◽  
Alex Winschel ◽  
Tobias Abel ◽  
Charlotte Bold ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Spine Density

scholarly journals Neuronal actin dynamics, spine density and neuronal dendritic complexity are regulated by CAP2

2015 ◽  
Author(s):  
Atul Kumar ◽  
Lars Paeger ◽  
Kosmas Kosmas ◽  
Peter Kloppenburg ◽  
Angelika Noegel ◽  
...  
Keyword(s):  
Dendritic Spine ◽  
Neuronal Development ◽  
Actin Dynamics ◽  
Spine Density ◽  
Delayed Wound Healing ◽  
Actin Remodeling ◽  
Cardiovascular Defects ◽  
Dendritic Complexity

Actin remodeling is indispensable for dendritic spine development, morphology and density which signify learning, memory and motor skills. CAP2 is a regulator of actin dynamics through sequestering G-actin and severing F-actin. In a mouse model, ablation of CAP2 leads to cardiovascular defects and delayed wound healing. This report investigates the role of CAP2 in the brain using Cap2gt/gt mice. Dendritic spine density and neuronal dendritic length were altered in Cap2gt/gt. This was accompanied by increased F-actin content and F-actin accumulation in cultured Cap2gt/gt neurons. In membrane depolarization assays, Cap2gt/gt synaptosomes exhibit an impaired F/G actin ratio, indicating altered actin dynamics. We show an interaction between CAP2 and n-cofilin, presumably mediated through the C-terminal domain of CAP2 and is cofilin ser3 phosphorylation dependent. In vivo, the consequences of this interaction were altered phosphorylated cofilin levels and formation of cofilin aggregates in the neurons. Thus, our studies identify a novel role of CAP2 in neuronal development and neuronal actin dynamics.

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

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.

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