12 results on '"Haensgen H"'
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2. Streuung polarisierter neutronen der energie 2.7 bis 2.9 MeV an kohlenstoff
- Author
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Hänsgen, H. and Nitzsche, M.
- Published
- 1971
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3. STUDY OF BERYLLIUM WITH POLARIZED NEUTRONS OF ENERGY 2.60 TO 2.77 Mev
- Author
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Haensgen, H
- Published
- 1966
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4. Deletion of VPS50 protein in mouse brain impairs synaptic function and behavior.
- Author
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Ahumada-Marchant C, Ancatén-Gonzalez C, Haensgen H, Brauer B, Merino-Veliz N, Droste R, Arancibia F, Horvitz HR, Constantine-Paton M, Arriagada G, Chávez AE, and Bustos FJ
- Subjects
- Animals, Mice, Behavior, Animal physiology, Brain metabolism, Neurons metabolism, Neurons physiology, Synapses metabolism, Synapses physiology, Synaptic Transmission, Vacuolar Proton-Translocating ATPases metabolism, Vacuolar Proton-Translocating ATPases genetics, Vesicular Transport Proteins genetics, Vesicular Transport Proteins metabolism, Mice, Knockout, Synaptic Vesicles metabolism
- Abstract
Background: The VPS50 protein functions in synaptic and dense core vesicle acidification, and perturbations of VPS50 function produce behavioral changes in Caenorhabditis elegans. Patients with mutations in VPS50 show severe developmental delay and intellectual disability, characteristics that have been associated with autism spectrum disorders (ASDs). The mechanisms that link VPS50 mutations to ASD are unknown., Results: To examine the role of VPS50 in mammalian brain function and behavior, we used the CRISPR/Cas9 system to generate knockouts of VPS50 in both cultured murine cortical neurons and living mice. In cultured neurons, KO of VPS50 did not affect the number of synaptic vesicles but did cause mislocalization of the V-ATPase V1 domain pump and impaired synaptic activity, likely as a consequence of defects in vesicle acidification and vesicle content. In mice, mosaic KO of VPS50 in the hippocampus altered synaptic transmission and plasticity and generated robust cognitive impairments., Conclusions: We propose that VPS50 functions as an accessory protein to aid the recruitment of the V-ATPase V1 domain to synaptic vesicles and in that way plays a crucial role in controlling synaptic vesicle acidification. Understanding the mechanisms controlling behaviors and synaptic function in ASD-associated mutations is pivotal for the development of targeted interventions, which may open new avenues for therapeutic strategies aimed at ASD and related conditions., (© 2024. The Author(s).)
- Published
- 2024
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5. Removal of a partial genomic duplication restores synaptic transmission and behavior in the MyosinVA mutant mouse Flailer.
- Author
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Bustos FJ, Pandian S, Haensgen H, Zhao JP, Strouf H, Heidenreich M, Swiech L, Deverman BE, Gradinaru V, Zhang F, and Constantine-Paton M
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- Mice, Animals, DNA Copy Number Variations, RNA, Guide, CRISPR-Cas Systems, Synaptic Transmission genetics, Genomics, Autism Spectrum Disorder genetics
- Abstract
Background: Copy number variations, and particularly duplications of genomic regions, have been strongly associated with various neurodegenerative conditions including autism spectrum disorder (ASD). These genetic variations have been found to have a significant impact on brain development and function, which can lead to the emergence of neurological and behavioral symptoms. Developing strategies to target these genomic duplications has been challenging, as the presence of endogenous copies of the duplicate genes often complicates the editing strategies., Results: Using the ASD and anxiety mouse model Flailer, which contains a partial genomic duplication working as a dominant negative for MyoVa, we demonstrate the use of DN-CRISPRs to remove a 700 bp genomic region in vitro and in vivo. Importantly, DN-CRISPRs have not been used to remove genomic regions using sgRNA with an offset greater than 300 bp. We found that editing the flailer gene in primary cortical neurons reverts synaptic transport and transmission defects. Moreover, long-term depression (LTD), disrupted in Flailer animals, is recovered after gene editing. Delivery of DN-CRISPRs in vivo shows that local delivery to the ventral hippocampus can rescue some of the mutant behaviors, while intracerebroventricular delivery, completely recovers the Flailer animal phenotype associated to anxiety and ASD., Conclusions: Our results demonstrate the potential of DN-CRISPR to efficiently remove larger genomic duplications, working as a new gene therapy approach for treating neurodegenerative diseases., (© 2023. BioMed Central Ltd., part of Springer Nature.)
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- 2023
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6. Deletion of VPS50 protein in mice brain impairs synaptic function and behavior.
- Author
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Ahumada-Marchant C, Ancatén-Gonzalez C, Haensgen H, Arancibia F, Brauer B, Droste R, Horvitz HR, Constantine-Paton M, Arriagada G, Chávez AE, and Bustos FJ
- Abstract
VPS50, is an accessory protein, involved in the synaptic and dense core vesicle acidification and its alterations produce behavioral changes in C.elegans. Here, we produce the mosaic knock out (mKO) of VPS50 using CRISPR/Cas9 system in both cortical cultured neurons and whole animals to evaluate the effect of VPS50 in regulating mammalian brain function and behavior. While mKO of VPS50 does not change the number of synaptic vesicles, it produces a mislocalization of the V-ATPase pump that likely impact in vesicle acidification and vesicle content to impair synaptic and neuronal activity in cultured neurons. In mice, mKO of VPS50 in the hippocampus, alter synaptic transmission and plasticity, and generated robust cognitive impairments associate to memory formation. We propose that VPS50 is an accessory protein that aids the correct recruitment of the V-ATPase pump to synaptic vesicles, thus having a crucial role controlling synaptic vesicle acidification and hence synaptic transmission., Competing Interests: Conflict of Interest: The authors declare no competing financial interests.
- Published
- 2023
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7. Removal of a genomic duplication by double-nicking CRISPR restores synaptic transmission and behavior in the MyosinVA mutant mouse Flailer.
- Author
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Bustos FJ, Pandian S, Haensgen H, Zhao JP, Strouf H, Heidenreich M, Swiech L, Deverman B, Gradinaru V, Zhang F, and Constantine-Paton M
- Abstract
Copy number variations, and particularly duplications of genomic regions, have been strongly associated with various neurodegenerative conditions including autism spectrum disorder (ASD). These genetic variations have been found to have a significant impact on brain development and function, which can lead to the emergence of neurological and behavioral symptoms. Developing strategies to target these genomic duplications has been challenging, as the presence of endogenous copies of the duplicate genes often complicates the editing strategies. Using the ASD and anxiety mouse model Flailer, that contains a duplication working as a dominant negative for MyoVa, we demonstrate the use of DN-CRISPRs to remove a 700bp genomic duplication in vitro and in vivo . Importantly, DN-CRISPRs have not been used to remove more gene regions <100bp successfully and with high efficiency. We found that editing the flailer gene in primary cortical neurons reverts synaptic transport and transmission defects. Moreover, long-term depression (LTD), disrupted in Flailer animals, is recovered after gene edition. Delivery of DN-CRISPRs in vivo shows that local delivery to the ventral hippocampus can rescues some of the mutant behaviors, while intracerebroventricular delivery, completely recovers Flailer animal phenotype associated to anxiety and ASD. Our results demonstrate the potential of DN-CRISPR to efficiently (>60% editing in vivo) remove large genomic duplications, working as a new gene therapy approach for treating neurodegenerative diseases.
- Published
- 2023
- Full Text
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8. Neurogranin, Encoded by the Schizophrenia Risk Gene NRGN, Bidirectionally Modulates Synaptic Plasticity via Calmodulin-Dependent Regulation of the Neuronal Phosphoproteome.
- Author
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Hwang H, Szucs MJ, Ding LJ, Allen A, Ren X, Haensgen H, Gao F, Rhim H, Andrade A, Pan JQ, Carr SA, Ahmad R, and Xu W
- Subjects
- Animals, Calmodulin metabolism, Hippocampus metabolism, Humans, Long-Term Potentiation, Mice, Neuronal Plasticity, Receptors, N-Methyl-D-Aspartate metabolism, Synapses metabolism, Neurogranin genetics, Neurogranin metabolism, Schizophrenia genetics
- Abstract
Background: Neurogranin (Ng), encoded by the schizophrenia risk gene NRGN, is a calmodulin-binding protein enriched in the postsynaptic compartments, and its expression is reduced in the postmortem brains of patients with schizophrenia. Experience-dependent translation of Ng is critical for encoding contextual memory, and Ng regulates developmental plasticity in the primary visual cortex during the critical period. However, the overall impact of Ng on the neuronal signaling that regulates synaptic plasticity is unknown., Methods: Altered Ng expression was achieved via virus-mediated gene manipulation in mice. The effect on long-term potentiation (LTP) was accessed using spike timing-dependent plasticity protocols. Quantitative phosphoproteomics analyses led to discoveries in significant phosphorylated targets. An identified candidate was examined with high-throughput planar patch clamp and was validated with pharmacological manipulation., Results: Ng bidirectionally modulated LTP in the hippocampus. Decreasing Ng levels significantly affected the phosphorylation pattern of postsynaptic density proteins, including glutamate receptors, GTPases, kinases, RNA binding proteins, selective ion channels, and ionic transporters, some of which highlighted clusters of schizophrenia- and autism-related genes. Hypophosphorylation of NMDA receptor subunit Grin2A, one significant phosphorylated target, resulted in accelerated decay of NMDA receptor currents. Blocking protein phosphatase PP2B activity rescued the accelerated NMDA receptor current decay and the impairment of LTP mediated by Ng knockdown, implicating the requirement of synaptic PP2B activity for the deficits., Conclusions: Altered Ng levels affect the phosphorylation landscape of neuronal proteins. PP2B activity is required for mediating the deficit in synaptic plasticity caused by decreasing Ng levels, revealing a novel mechanistic link of a schizophrenia risk gene to cognitive deficits., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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9. Rapid, experience-dependent translation of neurogranin enables memory encoding.
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Jones KJ, Templet S, Zemoura K, Kuzniewska B, Pena FX, Hwang H, Lei DJ, Haensgen H, Nguyen S, Saenz C, Lewis M, Dziembowska M, and Xu W
- Subjects
- Animals, Fear physiology, Fragile X Mental Retardation Protein metabolism, Hippocampus metabolism, Hippocampus physiology, Male, Mice, Mice, Inbred C57BL, Neurons metabolism, Neurons physiology, RNA, Messenger metabolism, Memory physiology, Neurogranin metabolism, Protein Biosynthesis physiology
- Abstract
Experience induces de novo protein synthesis in the brain and protein synthesis is required for long-term memory. It is important to define the critical temporal window of protein synthesis and identify newly synthesized proteins required for memory formation. Using a behavioral paradigm that temporally separates the contextual exposure from the association with fear, we found that protein synthesis during the transient window of context exposure is required for contextual memory formation. Among an array of putative activity-dependent translational neuronal targets tested, we identified one candidate, a schizophrenia-associated candidate mRNA, neurogranin (Ng, encoded by the Nrgn gene) responding to novel-context exposure. The Ng mRNA was recruited to the actively translating mRNA pool upon novel-context exposure, and its protein levels were rapidly increased in the hippocampus. By specifically blocking activity-dependent translation of Ng using virus-mediated molecular perturbation, we show that experience-dependent translation of Ng in the hippocampus is required for contextual memory formation. We further interrogated the molecular mechanism underlying the experience-dependent translation of Ng, and found that fragile-X mental retardation protein (FMRP) interacts with the 3'UTR of the Nrgn mRNA and is required for activity-dependent translation of Ng in the synaptic compartment and contextual memory formation. Our results reveal that FMRP-mediated, experience-dependent, rapid enhancement of Ng translation in the hippocampus during the memory acquisition enables durable context memory encoding., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)
- Published
- 2018
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10. Gestational Hypothyroxinemia Affects Its Offspring With a Reduced Suppressive Capacity Impairing the Outcome of the Experimental Autoimmune Encephalomyelitis.
- Author
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Haensgen H, Albornoz E, Opazo MC, Bugueño K, Jara Fernández EL, Binzberger R, Rivero-Castillo T, Venegas Salas LF, Simon F, Cabello-Verrugio C, Elorza AA, Kalergis AM, Bueno SM, and Riedel CA
- Subjects
- Adoptive Transfer, Animals, Biomarkers, Cell Differentiation, Cytokines metabolism, Encephalomyelitis, Autoimmune, Experimental pathology, Encephalomyelitis, Autoimmune, Experimental therapy, Female, Hypothyroidism blood, Hypothyroidism etiology, Immunophenotyping, Lymphocyte Activation, Lymphocyte Count, Methimazole administration & dosage, Methimazole adverse effects, Mice, Myelin Basic Protein metabolism, Phenotype, Pregnancy, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Thyrotropin blood, Thyroxine blood, Encephalomyelitis, Autoimmune, Experimental etiology, Encephalomyelitis, Autoimmune, Experimental metabolism, Hypothyroidism complications, Maternal Exposure adverse effects, Pregnancy Complications, Prenatal Exposure Delayed Effects
- Abstract
Hypothyroxinemia (Hpx) is a thyroid hormone deficiency (THD) condition highly frequent during pregnancy, which although asymptomatic for the mother, it can impair the cognitive function of the offspring. Previous studies have shown that maternal hypothyroidism increases the severity of experimental autoimmune encephalomyelitis (EAE), an autoimmune disease model for multiple sclerosis (MS). Here, we analyzed the immune response after EAE induction in the adult offspring gestated in Hpx. Mice gestated in Hpx showed an early appearance of EAE symptoms and the increase of all parameters of the disease such as: the pathological score, spinal cord demyelination, and immune cell infiltration in comparison to the adult offspring gestated in euthyroidism. Isolated CD4
+ CD25+ T cells from spleen of the offspring gestated in Hpx that suffer EAE showed reduced capacity to suppress proliferation of effector T cells (TEff ) after being stimulated with anti-CD3 and anti-CD28 antibodies. Moreover, adoptive transfer experiments of CD4+ CD25+ T cells from the offspring gestated in Hpx suffering EAE to mice that were induced with EAE showed that the receptor mice suffer more intense EAE pathological score. Even though, no significant differences were detected in the frequency of Treg cells and IL-10 content in the blood, spleen, and brain between mice gestated in Hpx or euthyroidism, T cells CD4+ CD25+ from spleen have reduced capacity to differentiate in vitro to Treg and to produce IL-10. Thus, our data support the notion that maternal Hpx can imprint the immune response of the offspring suffering EAE probably due to a reduced capacity to trigger suppression. Such "imprints" on the immune system could contribute to explaining as to why adult offspring gestated in Hpx suffer earlier and more intense EAE.- Published
- 2018
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11. NMDA receptor subunit composition controls dendritogenesis of hippocampal neurons through CAMKII, CREB-P, and H3K27ac.
- Author
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Bustos FJ, Jury N, Martinez P, Ampuero E, Campos M, Abarzúa S, Jaramillo K, Ibing S, Mardones MD, Haensgen H, Kzhyshkowska J, Tevy MF, Neve R, Sanhueza M, Varela-Nallar L, Montecino M, and van Zundert B
- Subjects
- Acetylation, Animals, Calcium-Calmodulin-Dependent Protein Kinase Type 2 antagonists & inhibitors, Calcium-Calmodulin-Dependent Protein Kinase Type 2 genetics, Cells, Cultured, Dendrites drug effects, Gestational Age, Hippocampus drug effects, Hippocampus embryology, Mutation, Peptides pharmacology, Phenotype, Protein Binding, Protein Interaction Domains and Motifs, Protein Kinase Inhibitors pharmacology, Protein Processing, Post-Translational, RNA Interference, Rats, Sprague-Dawley, Receptors, N-Methyl-D-Aspartate genetics, Signal Transduction, Transfection, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Cyclic AMP Response Element-Binding Protein metabolism, Dendrites enzymology, Hippocampus enzymology, Histones metabolism, Neurogenesis drug effects, Neuronal Plasticity drug effects, Receptors, N-Methyl-D-Aspartate metabolism
- Abstract
Dendrite arbor growth, or dendritogenesis, is choreographed by a diverse set of cues, including the NMDA receptor (NMDAR) subunits NR2A and NR2B. While NR1NR2B receptors are predominantly expressed in immature neurons and promote plasticity, NR1NR2A receptors are mainly expressed in mature neurons and induce circuit stability. How the different subunits regulate these processes is unclear, but this is likely related to the presence of their distinct C-terminal sequences that couple different signaling proteins. Calcium-calmodulin-dependent protein kinase II (CaMKII) is an interesting candidate as this protein can be activated by calcium influx through NMDARs. CaMKII triggers a series of biochemical signaling cascades, involving the phosphorylation of diverse targets. Among them, the activation of cAMP response element-binding protein (CREB-P) pathway triggers a plasticity-specific transcriptional program through unknown epigenetic mechanisms. Here, we found that dendritogenesis in hippocampal neurons is impaired by several well-characterized constructs (i.e., NR2B-RS/QD) and peptides (i.e., tatCN21) that specifically interfere with the recruitment and interaction of CaMKII with the NR2B C-terminal domain. Interestingly, we found that transduction of NR2AΔIN, a mutant NR2A construct with increased interaction to CaMKII, reactivates dendritogenesis in mature hippocampal neurons in vitro and in vivo. To gain insights into the signaling and epigenetic mechanisms underlying NMDAR-mediated dendritogenesis, we used immunofluorescence staining to detect CREB-P and acetylated lysine 27 of histone H3 (H3K27ac), an activation-associated histone tail mark. In contrast to control mature neurons, our data shows that activation of the NMDAR/CaMKII/ERK-P/CREB-P signaling axis in neurons expressing NR2AΔIN is not correlated with increased nuclear H3K27ac levels., (© 2017 Wiley Periodicals, Inc.)
- Published
- 2017
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12. Imprinting of maternal thyroid hormones in the offspring.
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Opazo MC, Haensgen H, Bohmwald K, Venegas LF, Boudin H, Elorza AA, Simon F, Fardella C, Bueno SM, Kalergis AM, and Riedel CA
- Subjects
- Animals, Cell Differentiation, Disease Susceptibility, Female, Humans, Hypothyroidism genetics, Mice, Mothers, Pregnancy, Pregnancy Complications genetics, Thyroid Hormones genetics, Central Nervous System physiology, Child of Impaired Parents, Encephalomyelitis, Autoimmune, Experimental, Hypothyroidism immunology, Sex Factors, Thyroid Hormones metabolism
- Abstract
Thyroid hormones (THs) during pregnancy contribute significantly to cellular differentiation and development in several tissues of the offspring, principally the central nervous system (CNS). TH deficiencies, such as hypothyroidism or hypothyroxinemia, are highly frequent during pregnancy worldwide and known to be detrimental for the development of the fetus. The function of CNS in the offspring gestated under TH deficiency will be irreversible impaired, causing low intellectual quotient, attention deficit, and mental retardation. On the other hand, little is known about the effects of TH deficiency in the offspring immune system, being the prevalent notion that the effects are reversible and only for a while will affect the number of B and T cells. Recent studies have shown that maternal hypothyroidism can altered the function of immune system in the offspring, rendering the female offspring more susceptible to suffer autoimmune-inflammatory diseases, such as experimental autoimmune encephalomyelitis (EAE) and to be more resistant to a bacterial infection. In this article we discuss these recent findings, as well as the possible mechanisms underlying these effects and the potential implications for human health.
- Published
- 2017
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