A Developmental Role for Microglial Presenilin 1 in Memory

SummaryMicroglia, the macrophages of the brain, are increasingly recognized to play a key role in synaptic plasticity and function; however, the underlying mechanisms remain elusive. Presenilin 1 (PS1) is an essential protein involved in learning and memory, through neuronal mechanisms. Loss of Presenilin function in neurons impairs synapse plasticity and causes cognitive deficits in mice. Surprisingly, here we show memory enhancement in mice by deleting PS1 selectively in microglia. We further demonstrate increased synapse transmission and in vivo neuronal activity in mice by depleting PS1 during microglial development, but not after microglial maturation. Remarkably, conditional deletion of PS1 in microglia during development increased memory retention in adulthood and was dependent on the NMDA receptor subunit GluN2B. In vivo calcium imaging of freely behaving mice revealed increased amplitude of neuronal Ca2+ transients in the CA1 hippocampus of PS1 cKO mice compared to control mice, suggesting a greater CA1 engagement during novel object exploration. Finally, loss of PS1 in microglia mitigated synaptic and cognitive deficits in a mouse model of Alzheimer’s disease. Together our results reveal a novel mechanism and function of PS1 in microglia in which modulation can enhance neuronal activity, learning and memory in mice.

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Expression of a Barhl1a reporter in subsets of retinal ganglion cells and commissural neurons of the developing zebrafish brain

10.1101/2020.02.20.957795 ◽

2020 ◽

Author(s):

Shahad Albadri ◽

Olivier Armant ◽

Tairi Aljand-Geschwill ◽

Filippo Del Bene ◽

Matthias Carl ◽

...

Keyword(s):

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Amacrine Cells ◽

Optic Chiasm ◽

Retinal Ganglion ◽

Commissural Neurons ◽

Axonal Projections ◽

Underlying Mechanisms ◽

And Function

AbstractPromoting the regeneration or survival of retinal ganglion cells (RGCs) is one focus of regenerative medicine. Homeobox Barhl transcription factors might be instrumental in these processes. In mammals, only barhl2 is expressed in the retina and is required for both subtype identity acquisition of amacrine cells and for the survival of RGCs downstream of Atoh7, a transcription factor necessary for RGC genesis. The underlying mechanisms of this dual role of Barhl2 in mammals have remained elusive. Whole genome duplication in the teleost lineage generated the barhl1a and barhl2 paralogues. In the Zebrafish retina, Barhl2 functions as determinant of subsets of amacrine cells lineally related to RGCs independently of Atoh7. In contrast, barhl1a expression depends on Atoh7 but its expression dynamics and function have not been studied. Here we describe for the first time a Barhl1a:GFP reporter line in vivo showing that Barhl1a turns on exclusively in subsets of RGCs and their post-mitotic precursors. We also show transient expression of Barhl1a:GFP in diencephalic neurons extending their axonal projections as part of the post-optic commissure, at the time of optic chiasm formation. This work sets the ground for future studies on RGC subtype identity, axonal projections and genetic specification of Barhl1a-positive RGCs and commissural neurons.

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Plants-Derived Neuroprotective Agents: Cutting the Cycle of Cell Death through Multiple Mechanisms

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/3574012 ◽

2017 ◽

Vol 2017 ◽

pp. 1-27 ◽

Cited By ~ 17

Author(s):

Taiwo Olayemi Elufioye ◽

Tomayo Ireti Berida ◽

Solomon Habtemariam

Keyword(s):

Mechanisms Of Action ◽

Neuroprotective Agents ◽

Structural Class ◽

Molecular Features ◽

Amyotropic Lateral Sclerosis ◽

Underlying Mechanisms ◽

And Function ◽

Lateral Sclerosis

Neuroprotection is the preservation of the structure and function of neurons from insults arising from cellular injuries induced by a variety of agents or neurodegenerative diseases (NDs). The various NDs including Alzheimer’s, Parkinson’s, and Huntington’s diseases as well as amyotropic lateral sclerosis affect millions of people around the world with the main risk factor being advancing age. Each of these diseases affects specific neurons and/or regions in the brain and involves characteristic pathological and molecular features. Hence, several in vitro and in vivo study models specific to each disease have been employed to study NDs with the aim of understanding their underlying mechanisms and identifying new therapeutic strategies. Of the most prevalent drug development efforts employed in the past few decades, mechanisms implicated in the accumulation of protein-based deposits, oxidative stress, neuroinflammation, and certain neurotransmitter deficits such as acetylcholine and dopamine have been scrutinized in great detail. In this review, we presented classical examples of plant-derived neuroprotective agents by highlighting their structural class and specific mechanisms of action. Many of these natural products that have shown therapeutic efficacies appear to be working through the above-mentioned key multiple mechanisms of action.

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Motor Learning Drives Dynamic Patterns of Intermittent Myelination on Behaviorally-Activated Axons

10.1101/2021.10.13.464319 ◽

2021 ◽

Author(s):

Clara M. Bacmeister ◽

Rongchen Huang ◽

Michael A. Thornton ◽

Lauren Conant ◽

Anthony R. Chavez ◽

...

Keyword(s):

Motor Learning ◽

Computational Modeling ◽

Learning And Memory ◽

Neuronal Activity ◽

Neural Circuits ◽

Cortical Layers ◽

Nodes Of Ranvier ◽

Two Photon ◽

Myelin Sheaths

Myelin plasticity occurs when newly-formed and pre-existing oligodendrocytes remodel existing myelination. Recent studies show these processes occur in response to changes in neuronal activity and are required for learning and memory. However, the link between behaviorally-relevant neuronal activity and circuit-specific changes in myelination remains unknown. Using longitudinal, in vivo two-photon imaging and targeted labeling of behaviorally-activated neurons, we explore how the pattern of intermittent myelination is altered on individual cortical axons during learning of a dexterous reach task. We show that learning-induced plasticity is targeted to behaviorally-activated axons and occurs in a staged response across cortical layers. During learning, myelin sheaths retract, lengthening nodes of Ranvier. Following learning, addition of new sheaths increases the number of continuous stretches of myelination. Computational modeling suggests these changes initially slow and subsequently increase conduction speed. Thus, behaviorally-activated, circuit-specific changes to myelination may fundamentally alter how information is transferred in neural circuits during learning.

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SNHG5 inhibits the progression of EMT through the ubiquitin-degradation of MTA2 in oesophageal cancer

Carcinogenesis ◽

10.1093/carcin/bgaa110 ◽

2020 ◽

Author(s):

Sisi Wei ◽

Shiping Sun ◽

Xinliang Zhou ◽

Cong Zhang ◽

Xiaoya Li ◽

...

Keyword(s):

Cell Lines ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Survival Rates ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Underlying Mechanisms ◽

And Function

Abstract A substantial fraction of transcripts are known as long noncoding RNAs (lncRNAs), and these transcripts play pivotal roles in the development of cancer. However, little information has been published regarding the functions of lncRNAs in oesophageal squamous cell carcinoma (ESCC) and the underlying mechanisms. In our previous studies, we demonstrated that small nucleolar RNA host gene 5 (SNHG5), a known lncRNA, is dysregulated in gastric cancer (GC). In this study, we explored the expression and function of SNHG5 in development of ESCC. SNHG5 was found to be downregulated in human ESCC tissues and cell lines, and this downregulation was associated with cancer progression, clinical outcomes and survival rates of ESCC patients. Furthermore, we also found that overexpression of SNHG5 significantly inhibited the proliferation, migration and invasion of ESCC cells in vivo and in vitro. Notably, we found that metastasis-associated protein 2 (MTA2) was pulled down by SNHG5 in ESCC cells using RNA pulldown assay. We also found that SNHG5 reversed the epithelial–mesenchymal transition by interacting with MTA2. In addition, overexpression of SNHG5 downregulated the transcription of MTA2 and caused its ubiquitin-mediated degradation. Thus, overexpression of MTA2 partially abrogated the effect of SNHG5 in ESCC cell lines. Furthermore, we found that MTA2 mRNA expression was significantly elevated in ESCC specimens, and a negative correlation between SNHG5 and MTA2 expression was detected. Overall, this study demonstrated, for the first time, that SNHG5-regulated MTA2 functions as an important player in the progression of ESCC and provide a new potential therapeutic strategy for ESCC.

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Brevican-Deficient Mice Display Impaired Hippocampal CA1 Long-Term Potentiation but Show No Obvious Deficits in Learning and Memory

Molecular and Cellular Biology ◽

10.1128/mcb.22.21.7417-7427.2002 ◽

2002 ◽

Vol 22 (21) ◽

pp. 7417-7427 ◽

Cited By ~ 170

Author(s):

Cord Brakebusch ◽

Constanze I. Seidenbecher ◽

Fredrik Asztely ◽

Uwe Rauch ◽

Henry Matthies ◽

...

Keyword(s):

Learning And Memory ◽

Long Term Potentiation ◽

Brain Anatomy ◽

Perineuronal Nets ◽

Functional Roles ◽

Term Potentiation ◽

And Function ◽

Deficient Mice

ABSTRACT Brevican is a brain-specific proteoglycan which is found in specialized extracellular matrix structures called perineuronal nets. Brevican increases the invasiveness of glioma cells in vivo and has been suggested to play a role in central nervous system fiber tract development. To study the role of brevican in the development and function of the brain, we generated mice lacking a functional brevican gene. These mice are viable and fertile and have a normal life span. Brain anatomy was normal, although alterations in the expression of neurocan were detected. Perineuronal nets formed but appeared to be less prominent in mutant than in wild-type mice. Brevican-deficient mice showed significant deficits in the maintenance of hippocampal long-term potentiation (LTP). However, no obvious impairment of excitatory and inhibitory synaptic transmission was found, suggesting a complex cause for the LTP defect. Detailed behavioral analysis revealed no statistically significant deficits in learning and memory. These data indicate that brevican is not crucial for brain development but has restricted structural and functional roles.

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Correction: Corbett et al., Sodium Channel Cleavage Is Associated with Aberrant Neuronal Activity and Cognitive Deficits in a Mouse Model of Alzheimer's Disease

Journal of Neuroscience ◽

10.1523/jneurosci.2235-13.2013 ◽

2013 ◽

Vol 33 (26) ◽

pp. 10934-10934 ◽

Cited By ~ 1

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Sodium Channel ◽

Neuronal Activity ◽

Cognitive Deficits ◽

Model Of Alzheimer’S Disease

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The Role of Mitochondria in Optic Atrophy With Autosomal Inheritance

Frontiers in Neuroscience ◽

10.3389/fnins.2021.784987 ◽

2021 ◽

Vol 15 ◽

Author(s):

Elin L. Strachan ◽

Delphi Mac White-Begg ◽

John Crean ◽

Alison L. Reynolds ◽

Breandán N. Kennedy ◽

...

Keyword(s):

Optic Atrophy ◽

Ganglion Cells ◽

Treatment Development ◽

Loss Of Vision ◽

Ocular Symptoms ◽

High Prevalence ◽

Underlying Mechanisms ◽

And Function ◽

Autosomal Inheritance

Optic atrophy (OA) with autosomal inheritance is a form of optic neuropathy characterized by the progressive and irreversible loss of vision. In some cases, this is accompanied by additional, typically neurological, extra-ocular symptoms. Underlying the loss of vision is the specific degeneration of the retinal ganglion cells (RGCs) which form the optic nerve. Whilst autosomal OA is genetically heterogenous, all currently identified causative genes appear to be associated with mitochondrial organization and function. However, it is unclear why RGCs are particularly vulnerable to mitochondrial aberration. Despite the relatively high prevalence of this disorder, there are currently no approved treatments. Combined with the lack of knowledge concerning the mechanisms through which aberrant mitochondrial function leads to RGC death, there remains a clear need for further research to identify the underlying mechanisms and develop treatments for this condition. This review summarizes the genes known to be causative of autosomal OA and the mitochondrial dysfunction caused by pathogenic mutations. Furthermore, we discuss the suitability of available in vivo models for autosomal OA with regards to both treatment development and furthering the understanding of autosomal OA pathology.

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Icariside II, a Phosphodiesterase-5 Inhibitor, Attenuates Beta-Amyloid-Induced Cognitive Deficits via BDNF/TrkB/CREB Signaling

Cellular Physiology and Biochemistry ◽

10.1159/000493232 ◽

2018 ◽

Vol 49 (3) ◽

pp. 1010-1025 ◽

Cited By ~ 5

Author(s):

Shuang Liu ◽

Xiaohui Li ◽

Jianmei Gao ◽

Yuangui Liu ◽

Jingshan Shi ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Cognitive Deficits ◽

Cell Injury ◽

Intracellular Reactive Oxygen Species ◽

Oxygen Species ◽

Mitochondrial Ros ◽

Icariside Ii ◽

Underlying Mechanisms ◽

Phosphodiesterase 5

Background/Aims: Icariside II (ICS II) is an active component from Epimedium brevicornum, a Chinese medicine extensively used in China. Our previous study has proved that ICS II protects against learning and memory impairments and neuronal apoptosis in the hippocampus induced by beta-amyloid25-35 (Aβ25-35) in rats. However, its in-depth underlying mechanisms remain still unclear. Hence this study was designed to explore the potential underlying mechanisms of ICS II by experiments with an in vivo model of Aβ25-35-induced cognitive deficits in rats combined with a neuronal-like PC12 cells injury in vitro model. Methods: The cognitive deficits was measured using Morris water maze test, and apoptosis, intracellular reactive oxygen species (ROS) and mitochondrial ROS levels were detected by TUNEL, DCFH-DA and Mito-SOX staining, respectively. Expression of Bcl-2, Bax, brain derived neurotrophic factor (BDNF), tyrosine receptor kinase B (TrkB), and cAMP response element binding (p-CREB) and active-Caspase 3 levels were evaluated by Western blot. Results: It was found that ICS II, a phosphodiesterase-5 inhibitor, significantly attenuated cognitive deficits caused by Aβ25-35 injection in rats, and ICS II not only significantly enhanced the expression of BDNF and TrkB, but also activated CREB. Furthermore, ICS II also significantly abrogated Aβ25-35-induced PC12 cell injury, and inhibited Aβ25-35-induced intracellular reactive oxygen species (ROS) overproduction, as well as mitochondrial ROS levels. In addition, ICS II up-regulated the expressions of BDNF and TrkB consistent with the findings in vivo. ANA-12, a TrkB inhibitor, blocked the neuroprotective effect of ICS II on Aβ25-35-induced neuronal injury. Conclusion: ICS II mitigates Aβ25-35-induced cognitive deficits and neuronal cell injury by upregulating the BDNF/TrkB/CREB signaling, suggesting that ICS II can be used as a potential therapeutic agent for dementia, such as Alzheimer’s disease.

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