scholarly journals Depression-Associated Gene Negr1-Fgfr2 Pathway Is Altered by Antidepressant Treatment

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1818
Author(s):  
Lucia Carboni ◽  
Francesca Pischedda ◽  
Giovanni Piccoli ◽  
Mario Lauria ◽  
Laura Musazzi ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
Hippocampal Neurons ◽  
Antidepressant Treatment ◽  
Primary Neurons ◽  
Expression Of Genes ◽  
Family Protein ◽  
Adam10 Expression ◽  
A Cell ◽  
Sensitive Line ◽  
Spine Plasticity

The Negr1 gene has been significantly associated with major depression in genetic studies. Negr1 encodes for a cell adhesion molecule cleaved by the protease Adam10, thus activating Fgfr2 and promoting neuronal spine plasticity. We investigated whether antidepressants modulate the expression of genes belonging to Negr1-Fgfr2 pathway in Flinders sensitive line (FSL) rats, in a corticosterone-treated mouse model of depression, and in mouse primary neurons. Negr1 and Adam10 were the genes mostly affected by antidepressant treatment, and in opposite directions. Negr1 was down-regulated by escitalopram in the hypothalamus of FSL rats, by fluoxetine in the hippocampal dentate gyrus of corticosterone-treated mice, and by nortriptyline in hippocampal primary neurons. Adam10 mRNA was increased by nortriptyline administration in the hypothalamus, by escitalopram in the hippocampus of FSL rats, and by fluoxetine in mouse dorsal dentate gyrus. Similarly, nortriptyline increased Adam10 expression in hippocampal cultures. Fgfr2 expression was increased by nortriptyline in the hypothalamus of FSL rats and in hippocampal neurons. Lsamp, another IgLON family protein, increased in mouse dentate gyrus after fluoxetine treatment. These findings suggest that Negr1-Fgfr2 pathway plays a role in the modulation of synaptic plasticity induced by antidepressant treatment to promote therapeutic efficacy by rearranging connectivity in corticolimbic circuits impaired in depression.

scholarly journals A Super-Resolved View of the Alzheimer’s Disease-Related Amyloidogenic Pathway in Hippocampal Neurons

2021 ◽  
pp. 1-20
Author(s):  
Yang Yu ◽  
Yang Gao ◽  
Bengt Winblad ◽  
Lars Tjernberg ◽  
Sophia Schedin Weiss
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hippocampal Neurons ◽  
Three Dimensional ◽  
Amyloid Β ◽  
Stimulated Emission ◽  
Amyloid Β Peptide ◽  
Primary Neurons ◽  
Amyloid Β Protein ◽  
Early Endosomes

Background: Processing of the amyloid-β protein precursor (AβPP) is neurophysiologically important due to the resulting fragments that regulate synapse biology, as well as potentially harmful due to generation of the 42 amino acid long amyloid β-peptide (Aβ 42), which is a key player in Alzheimer’s disease. Objective: Our aim was to clarify the subcellular locations of the amyloidogenic AβPP processing in primary neurons, including the intracellular pools of the immediate substrate, AβPP C-terminal fragment (APP-CTF) and the product (Aβ 42). To overcome the difficulties of resolving these compartments due to their small size, we used super-resolution microscopy. Methods: Mouse primary hippocampal neurons were immunolabelled and imaged by stimulated emission depletion (STED) microscopy, including three-dimensional, three-channel imaging and image analyses. Results: The first (β-secretase) and second (γ-secretase) cleavages of AβPP were localized to functionally and distally distinct compartments. The β-secretase cleavage was observed in early endosomes, where we were able to show that the liberated N- and C-terminal fragments were sorted into distinct vesicles budding from the early endosomes in soma. Lack of colocalization of Aβ 42 and APP-CTF in soma suggested that γ-secretase cleavage occurs in neurites. Indeed, APP-CTF was, in line with Aβ 42 in our previous study, enriched in the presynapse but absent from the postsynapse. In contrast, full-length AβPP was not detected in either the pre- or the postsynaptic side of the synapse. Furthermore, we observed that endogenously produced and endocytosed Aβ 42 were localized in different compartments. Conclusion: These findings provide critical super-resolved insight into amyloidogenic AβPP processing in primary neurons.

scholarly journals Haploinsufficiency of the psychiatric risk gene Cyfip1 causes abnormal postnatal hippocampal neurogenesis through microglial and Arp2/3 mediated actin dependent mechanisms

2018 ◽  
Author(s):  
Niels Haan ◽  
Laura J Westacott ◽  
Jenny Carter ◽  
Michael J Owen ◽  
William P Gray ◽  
...  
Keyword(s):  
Genetic Risk ◽  
Hippocampal Neurons ◽  
Hippocampal Neurogenesis ◽  
Actin Dynamics ◽  
Biological Processes ◽  
Risk Gene ◽  
A Cell ◽  
Adult Born Neurons ◽  
Newborn Neurons ◽  
And Migration

AbstractGenetic risk factors can significantly increase chances of developing psychiatric disorders, but the underlying biological processes through which this risk is effected remain largely unknown. Here we show that haploinsufficiency of Cyfip1, a candidate risk gene present in the pathogenic 15q11.2(BP1-BP2) deletion may impact on psychopathology via abnormalities in cell survival and migration of newborn neurons during postnatal hippocampal neurogenesis. We demonstrate that haploinsufficiency of Cyfip1 leads to increased numbers of adult born hippocampal neurons due to reduced apoptosis, without altering proliferation. We confirm this is due to a cell autonomous failure of microglia to induce apoptosis through the secretion of the appropriate factors. Furthermore, we show an abnormal migration of adult-born neurons due to altered Arp2/3 mediated actin dynamics. Together, our findings throw new light on how the genetic risk candidate Cyfip1 may influence the hippocampus, a brain region with strong evidence for involvement in psychopathology.

scholarly journals Neuron-based high-content assay and screen for CNS active mitotherapeutics

2020 ◽  
Vol 6 (2) ◽  
pp. eaaw8702 ◽  
Author(s):  
Boglarka H. Varkuti ◽  
Miklos Kepiro ◽  
Ze Liu ◽  
Kyle Vick ◽  
Yosef Avchalumov ◽  
...  
Keyword(s):  
Small Molecule ◽  
Hippocampal Neurons ◽  
Mitochondrial Dynamics ◽  
Synaptic Activity ◽  
Glutamate Toxicity ◽  
Primary Neurons ◽  
Screening Assay ◽  
Dynamics And Function ◽  
Small Molecule Modulators ◽  
And Function

Impaired mitochondrial dynamics and function are hallmarks of many neurological and psychiatric disorders, but direct screens for mitotherapeutics using neurons have not been reported. We developed a multiplexed and high-content screening assay using primary neurons and identified 67 small-molecule modulators of neuronal mitostasis (MnMs). Most MnMs that increased mitochondrial content, length, and/or health also increased mitochondrial function without altering neurite outgrowth. A subset of MnMs protected mitochondria in primary neurons from Aβ(1–42) toxicity, glutamate toxicity, and increased oxidative stress. Some MnMs were shown to directly target mitochondria. The top MnM also increased the synaptic activity of hippocampal neurons and proved to be potent in vivo, increasing the respiration rate of brain mitochondria after administering the compound to mice. Our results offer a platform that directly queries mitostasis processes in neurons, a collection of small-molecule modulators of mitochondrial dynamics and function, and candidate molecules for mitotherapeutics.

scholarly journals Seizure-related 6 homolog like 2 autoimmunity

2020 ◽  
Vol 8 (1) ◽  
pp. e916
Author(s):  
Jon Landa ◽  
Mar Guasp ◽  
Mar Petit-Pedrol ◽  
Eugenia Martínez-Hernández ◽  
Jesús Planagumà ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Brain Mri ◽  
Index Patient ◽  
Clinical Syndrome ◽  
Extrapyramidal Symptoms ◽  
Hek293 Cells ◽  
Neuronal Cultures ◽  
Neurologic Disorders ◽  
A Cell ◽  
Csf Pleocytosis

ObjectiveTo describe the clinical syndrome of 4 new patients with seizure-related 6 homolog like 2 antibodies (SEZ6L2-abs), study the antibody characteristics, and evaluate their effects on neuronal cultures.MethodsSEZ6L2-abs were initially identified in serum and CSF of a patient with cerebellar ataxia by immunohistochemistry on rat brain sections and immunoprecipitation from rat cerebellar neurons. We used a cell-based assay (CBA) of HEK293 cells transfected with SEZ6L2 to test the serum of 95 patients with unclassified neuropil antibodies, 331 with different neurologic disorders, and 10 healthy subjects. Additional studies included characterization of immunoglobulin G (IgG) subclasses and the effects of SEZ6L2-abs on cultures of rat hippocampal neurons.ResultsIn addition to the index patient, SEZ6L2-abs were identified by CBA in 3/95 patients with unclassified neuropil antibodies but in none of the 341 controls. The median age of the 4 patients was 62 years (range: 54–69 years), and 2 were female. Patients presented with subacute gait ataxia, dysarthria, and mild extrapyramidal symptoms. Initial brain MRI was normal, and CSF pleocytosis was found in only 1 patient. None improved with immunotherapy. SEZ6L2-abs recognized conformational epitopes. IgG4 SEZ6L2-abs were found in all 4 patients, and it was the predominant subclass in 2. SEZ6L2-abs did not alter the number of total or synaptic SEZ6L2 or the AMPA glutamate receptor 1 (GluA1) clusters on the surface of hippocampal neurons.ConclusionsSEZ6L2-abs associate with a subacute cerebellar syndrome with frequent extrapyramidal symptoms. The potential pathogenic effect of the antibodies is not mediated by internalization of the antigen.

scholarly journals INCREASE IN HSP25 EXTENDS LIFESPAN AND IMPROVES RESPONSE TO TAU TOXICITY THROUGH A CELL, NON-AUTONOMOUS MECHANISM

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S730-S730
Author(s):  
Karl Rodriguez
Keyword(s):  
Stress Response ◽  
Protein Aggregation ◽  
Cell Types ◽  
Over Expression ◽  
C Elegans ◽  
Expression Of Genes ◽  
Stress Response Pathway ◽  
A Cell ◽  
Cytotoxic Proteins ◽  
Improve Health

Abstract The accrual of aggregation-prone cytotoxic proteins underlies neural pathologies seen in aging, Alzheimer’s disease and other dementias. Recent evidence indicates that heat shock protein 25kDa (HSP25) interacts with tau. To demonstrate a causal role for HSP25 in these pathologies, we overexpressed HSP25 protein in worms. This manipulation led to an increase in life span. Moreover, the longevity-effect was associated with increased expression of genes downstream of the SKN-1/Nrf2 stress-response transcription factor. HSP25 over-expression also reduces aggregate pathology and extends lifespan in a C. elegans neuronal-specific, aggregate-prone tau model . We propose that over-expression of HSP25 could provide protection from protein aggregation induced neurodegeneration. However, it is not yet clear whether this HSP25 effect could be efficaciously provided exogenously by other cell types. Thus, we will test whether increased peripheral HSP25 will reduce protein aggregation and stimulate a global Skn-1 stress-response pathway, reduce toxicity in neurons, and improve health outcomes.

scholarly journals In vivo two-photon imaging of mouse hippocampal neurons in dentate gyrus using a light source based on a high-peak power gain-switched laser diode

2015 ◽  
Vol 6 (3) ◽  
pp. 891 ◽  
Author(s):  
Ryosuke Kawakami ◽  
Kazuaki Sawada ◽  
Yuta Kusama ◽  
Yi-Cheng Fang ◽  
Shinya Kanazawa ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
Light Source ◽  
Laser Diode ◽  
Hippocampal Neurons ◽  
Peak Power ◽  
High Peak ◽  
High Peak Power ◽  
Power Gain ◽  
Two Photon

scholarly journals LuxR-family ‘solos’: bachelor sensors/regulators of signalling molecules

Microbiology ◽  
2009 ◽  
Vol 155 (5) ◽  
pp. 1377-1385 ◽  
Author(s):  
Sujatha Subramoni ◽  
Vittorio Venturi
Keyword(s):  
Bacterial Species ◽  
Signalling Molecules ◽  
Acylhomoserine Lactone ◽  
Family Protein ◽  
Density Response ◽  
A Cell ◽  
Biochemical Mechanisms ◽  
Molecular And Biochemical Mechanisms ◽  
Interkingdom Communication ◽  
Mixed Communities

N-Acylhomoserine lactone (AHL) quorum-sensing (QS) signalling is the best-understood chemical language in proteobacteria. In the last 15 years a large amount of research in several bacterial species has revealed in detail the genetic, molecular and biochemical mechanisms underlying AHL signalling. These studies have revealed the role played by protein pairs of the AHL synthase belonging to the LuxI family and cognate LuxR-family AHL sensor–regulator. Proteobacteria however commonly possess a QS LuxR-family protein for which there is no obvious cognate LuxI synthase; these proteins are found in bacteria which possess a complete AHL QS system(s) as well as in bacteria that do not. Scientists are beginning to address the roles played by these proteins and it is emerging that they could allow bacteria to respond to endogenous and exogenous signals produced by their neighbours. AHL QS research thus far has mainly focused on a cell-density response involving laboratory monoculture studies. Recent findings on the role played by the unpaired LuxR-family proteins highlight the need to address bacterial behaviour and response to signals in mixed communities. Here we review recent progress with respect to these LuxR proteins, which we propose to call LuxR ‘solos’ since they act on their own without the need for a cognate signal generator. Initial investigations have revealed that LuxR solos have diverse roles in bacterial interspecies and interkingdom communication.

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