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1.
Transl Neurosci ; 15(1): 20220330, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38283997

RESUMO

Objective: Heterozygous mutations within the voltage-gated sodium channel α subunit (SCN1A) are responsible for the majority of cases of Dravet syndrome (DS), a severe developmental and epileptic encephalopathy. Development of novel therapeutic approaches is mandatory in order to directly target the molecular consequences of the genetic defect. The aim of the present study was to investigate whether cis-acting long non-coding RNAs (lncRNAs) of SCN1A are expressed in brain specimens of children and adolescent with epilepsy as these molecules comprise possible targets for precision-based therapy approaches. Methods: We investigated SCN1A mRNA expression and expression of two SCN1A related antisense RNAs in brain tissues in different age groups of pediatric non-Dravet patients who underwent surgery for drug resistant epilepsy. The effect of different antisense oligonucleotides (ASOs) directed against SCN1A specific antisense RNAs on SCN1A expression was tested. Results: The SCN1A related antisense RNAs SCN1A-dsAS (downstream antisense, RefSeq identifier: NR_110598) and SCN1A-usAS (upstream AS, SCN1A-AS, RefSeq identifier: NR_110260) were widely expressed in the brain of pediatric patients. Expression patterns revealed a negative correlation of SCN1A-dsAS and a positive correlation of lncRNA SCN1A-usAS with SCN1A mRNA expression. Transfection of SK-N-AS cells with an ASO targeted against SCN1A-dsAS was associated with a significant enhancement of SCN1A mRNA expression and reduction in SCN1A-dsAS transcripts. Conclusion: These findings support the role of SCN1A-dsAS in the suppression of SCN1A mRNA generation. Considering the haploinsufficiency in genetic SCN1A related DS, SCN1A-dsAS is an interesting target candidate for the development of ASOs (AntagoNATs) based precision medicine therapeutic approaches aiming to enhance SCN1A expression in DS.

2.
Basic Res Cardiol ; 117(1): 44, 2022 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-36068417

RESUMO

Myocardial infarction (MI) with subsequent depression is associated with increased cardiac mortality. Impaired central mineralocorticoid (MR) and glucocorticoid receptor (GR) equilibrium has been suggested as a key mechanism in the pathogenesis of human depression. Here, we investigate if deficient central MR/GR signaling is causative for a poor outcome after MI in mice. Mice with an inducible forebrain-specific MR/GR knockout (MR/GR-KO) underwent baseline and follow-up echocardiography every 2 weeks after MI or sham operation. Behavioral testing at 4 weeks confirmed significant depressive-like behavior and, strikingly, a higher mortality after MI, while cardiac function and myocardial damage remained unaffected. Telemetry revealed cardiac autonomic imbalance with marked bradycardia and ventricular tachycardia (VT) upon MI in MR/GR-KO. Mechanistically, we found a higher responsiveness to atropine, pointing to impaired parasympathetic tone of 'depressive' mice after MI. Serum corticosterone levels were increased but-in line with the higher vagal tone-plasma and cardiac catecholamines were decreased. MR/GR deficiency in the forebrain led to significant depressive-like behavior and a higher mortality after MI. This was accompanied by increased vagal tone, depleted catecholaminergic compensatory capacity and VTs. Thus, limbic MR/GR disequilibrium may contribute to the impaired outcome of depressive patients after MI and possibly explain the lack of anti-depressive treatment benefit.


Assuntos
Depressão , Infarto do Miocárdio , Animais , Humanos , Camundongos , Infarto do Miocárdio/patologia , Miocárdio/patologia , Prosencéfalo/metabolismo , Receptores de Glucocorticoides/metabolismo
3.
EMBO J ; 41(4): e109108, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35019161

RESUMO

Haploinsufficiency of the progranulin (PGRN)-encoding gene (GRN) causes frontotemporal lobar degeneration (GRN-FTLD) and results in microglial hyperactivation, TREM2 activation, lysosomal dysfunction, and TDP-43 deposition. To understand the contribution of microglial hyperactivation to pathology, we used genetic and pharmacological approaches to suppress TREM2-dependent transition of microglia from a homeostatic to a disease-associated state. Trem2 deficiency in Grn KO mice reduced microglia hyperactivation. To explore antibody-mediated pharmacological modulation of TREM2-dependent microglial states, we identified antagonistic TREM2 antibodies. Treatment of macrophages from GRN-FTLD patients with these antibodies led to reduced TREM2 signaling due to its enhanced shedding. Furthermore, TREM2 antibody-treated PGRN-deficient microglia derived from human-induced pluripotent stem cells showed reduced microglial hyperactivation, TREM2 signaling, and phagocytic activity, but lysosomal dysfunction was not rescued. Similarly, lysosomal dysfunction, lipid dysregulation, and glucose hypometabolism of Grn KO mice were not rescued by TREM2 ablation. Synaptic loss and neurofilament light-chain (NfL) levels, a biomarker for neurodegeneration, were further elevated in the Grn/Trem2 KO cerebrospinal fluid (CSF). These findings suggest that TREM2-dependent microglia hyperactivation in models of GRN deficiency does not promote neurotoxicity, but rather neuroprotection.


Assuntos
Degeneração Lobar Frontotemporal/patologia , Glicoproteínas de Membrana/metabolismo , Microglia/fisiologia , Monócitos/metabolismo , Progranulinas/deficiência , Receptores Imunológicos/metabolismo , Animais , Anticorpos/imunologia , Anticorpos/farmacologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Feminino , Degeneração Lobar Frontotemporal/metabolismo , Humanos , Lisossomos/metabolismo , Lisossomos/patologia , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Quinase Syk/metabolismo
4.
Front Psychiatry ; 12: 750106, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34899420

RESUMO

Extensive evidence suggests a dysfunction of the glutamate NMDA receptor (NMDAR) in schizophrenia, a severe psychiatric disorder with putative early neurodevelopmental origins, but clinical onset mainly during late adolescence. On the other hand, pharmacological models using NMDAR antagonists and the clinical manifestation of anti-NMDAR encephalitis indicate that NMDAR blockade/hypofunction can trigger psychosis also at adult stages, without any early developmental dysfunction. Previous genetic models of NMDAR hypofunction restricted to parvalbumin-positive interneurons indicate the necessity of an early postnatal impairment to trigger schizophrenia-like abnormalities, whereas the cellular substrates of NMDAR-mediated psychosis at adolescent/adult stages are unknown. Neuregulin 1 (NRG1) and its receptor ErbB4 represent schizophrenia-associated susceptibility factors that closely interact with NMDAR. To determine the neuronal populations implicated in "late" NMDAR-driven psychosis, we analyzed the effect of the inducible ablation of NMDARs in ErbB4-expressing cells in mice during late adolescence using a pharmacogenetic approach. Interestingly, the tamoxifen-inducible NMDAR deletion during this late developmental stage did not induce behavioral alterations resembling depression, schizophrenia or anxiety. Our data indicate that post-adolescent NMDAR deletion, even in a wider cell population than parvalbumin-positive interneurons, is also not sufficient to generate behavioral abnormalities resembling psychiatric disorders. Other neuronal substrates that have to be revealed by future studies, may underlie post-adolescent NMDAR-driven psychosis.

5.
Animals (Basel) ; 11(5)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34066005

RESUMO

Ensuring optimal housing conditions for laboratory animals is a crucial prerequisite for high-quality and ethically justifiable in vivo science. In addition to guaranteeing animal welfare and promoting scientific validity, environmental sustainability is also increasingly gaining attention in laboratory animal facilities. Consequently, comprehensive management of such aspects is one of the core tasks of any research vivarium. Hygienic monitoring and adhering to standardized experimental protocols have been highlighted in the past; nevertheless, various environmental aspects of housing animals still need to be evaluated in greater depth. In this pilot study, we aimed at assessing the suitability of spelt and corncob as economical and ecologically friendly bedding substrates as compared with commonly used aspen wood chips. Therefore, following a descriptive study design, we examined the preferences of male and female Wistar rats for corncob and spelt under specific conditions. In addition, we evaluated potential effects on behavior, metabolism, and stress physiology. The type of bedding did not seem to influence behavior in the observed parameters but did have time- and sex-dependent effects on blood glucose. Furthermore, housing animals on spelt led to a significant reduction in food consumption, probably compensated for by the intake of spelt, and although it did not influence glucose levels, it may have certainly impacted the nutrient supply. Our descriptive pilot study, therefore, highlights the importance of a thorough condition-associated evaluation of even seemingly marginal environmental factors, when balancing potential cost-benefit advances in sustainability and questions of standardization and reproducibility of experimental protocols.

6.
Proc Natl Acad Sci U S A ; 117(3): 1753-1761, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31896584

RESUMO

Carbon dioxide (CO2), the major product of metabolism, has a strong impact on cerebral blood vessels, a phenomenon known as cerebrovascular reactivity. Several vascular risk factors such as hypertension or diabetes dampen this response, making cerebrovascular reactivity a useful diagnostic marker for incipient vascular pathology, but its functional relevance, if any, is still unclear. Here, we found that GPR4, an endothelial H+ receptor, and endothelial Gαq/11 proteins mediate the CO2/H+ effect on cerebrovascular reactivity in mice. CO2/H+ leads to constriction of vessels in the brainstem area that controls respiration. The consequential washout of CO2, if cerebrovascular reactivity is impaired, reduces respiration. In contrast, CO2 dilates vessels in other brain areas such as the amygdala. Hence, an impaired cerebrovascular reactivity amplifies the CO2 effect on anxiety. Even at atmospheric CO2 concentrations, impaired cerebrovascular reactivity caused longer apneic episodes and more anxiety, indicating that cerebrovascular reactivity is essential for normal brain function. The site-specific reactivity of vessels to CO2 is reflected by regional differences in their gene expression and the release of vasoactive factors from endothelial cells. Our data suggest the central nervous system (CNS) endothelium as a target to treat respiratory and affective disorders associated with vascular diseases.


Assuntos
Ansiedade/metabolismo , Sistema Cardiovascular/metabolismo , Endotélio/metabolismo , Transtornos Respiratórios/metabolismo , Tonsila do Cerebelo , Animais , Arteríolas/patologia , Encéfalo/fisiologia , Tronco Encefálico/metabolismo , Dióxido de Carbono/metabolismo , Sistema Nervoso Central/metabolismo , Modelos Animais de Doenças , Endotélio/patologia , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Expressão Gênica , Humanos , Hipercapnia/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Respiração , Fatores de Risco , Transdução de Sinais
7.
Lab Anim ; 54(1): 40-49, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31575329

RESUMO

Animal models in psychiatric research are indispensable for insights into mechanisms of behaviour and mental disorders. Distress is an important aetiological factor in psychiatric diseases, especially depression, and is often used to mimic the human condition. Modern bioethics requires balancing scientific progress with animal welfare concerns. Therefore, scientifically based severity assessment of procedures is a prerequisite for choosing the least compromising paradigm according to the 3Rs principle. Evidence-based severity assessment in psychiatric animal models is scarce, particularly in depression research. Here, we assessed severity in a cognitive depression model by analysing indicators of stress and well-being, including physiological (body weight and corticosterone metabolite concentrations) and behavioural (nesting and burrowing behaviour) parameters. Additionally, a novel approach for objective individualised severity grading was employed using clustering of voluntary wheel running (VWR) behaviour. Exposure to the paradigm evoked a transient elevation of corticosterone, but neither affected body weight, nesting or burrowing behaviour. However, the performance in VWR was impaired after recurrent stress exposure, and the individual severity level increased, indicating that this method is more sensitive in detecting compromised welfare. Interestingly, the direct comparison to a somatic, chemically induced colitis model indicates less distress in the depression model. Further objective severity assessment studies are needed to classify the severity of psychiatric animal models in order to balance validity and welfare, reduce the stress load and thus promote refinement.


Assuntos
Peso Corporal , Corticosterona/metabolismo , Depressão/classificação , Desamparo Aprendido , Comportamento de Nidação , Índice de Gravidade de Doença , Estresse Psicológico , Bem-Estar do Animal , Animais , Modelos Animais de Doenças , Camundongos
8.
PLoS One ; 14(4): e0215367, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30978250

RESUMO

Mice are social animals hence group-housing of mice is preferred over individual housing. However, aggression in group-housed male mice under laboratory housing conditions is a well-known problem leading to serious health issues, including injury or death. Therefore, group-housed mice are frequently separated for welfare reasons. In this study, we investigated the effect of 3 different handling methods (tail, forceps, tube) in 2 different housing conditions (single vs. group) on the variance of aggression-associated parameters in male C57BL/6NCrl mice over 8 weeks. Blood glucose concentration, body weight, body temperature, plus number and severity of bite wounds and barbering intensity in group-housed mice were recorded. An assessment of nest complexity was also performed weekly. Feces were collected in week 3 and 7 for analysis of corticosterone metabolites. We also monitored the level of aggression by recording the behavior of group-housed animals after weekly cage cleaning. An open field test followed by a social novel object test, a light/dark box test, a hotplate and a resident-intruder test were performed at the end of the 8-week handling period. Post-mortem, we assessed organ weights. We found that forceps-handled mice, independent of the housing condition, had significantly higher levels of stress-induced-hyperthermia and enhanced aggression after cage cleaning, and they performed worse in the nest complexity test. In addition, handling male mice by the tail seems to be most effective to reduce aggressiveness after transferring animals into new cages, thereby representing an appropriate refinement.


Assuntos
Agressão/psicologia , Criação de Animais Domésticos/métodos , Comportamento Animal/fisiologia , Abrigo para Animais , Agressão/fisiologia , Animais , Corticosterona/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Comportamento Social , Estresse Fisiológico
9.
ESC Heart Fail ; 6(4): 711-722, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31025825

RESUMO

AIMS: Myocardial infarction (MI) and heart failure (HF) are risk factors for the development of depression, additionally worsening the quality of life and patient outcome. How HF causes depression and how depression promotes HF remain mechanistically unclear, which is at least partly caused by the difficulty of in vivo modelling of psychosomatic co-morbidity. We aimed to study the potential sequence of events with respect to different depression aspects upon HF. METHODS AND RESULTS: Male C57BL6 mice underwent MI, followed by behavioural and echocardiographic characterization. Motility, exploration, and anxiety-like behaviour were unaffected in mice after MI. We did not observe increased depressive-like behaviour in the sucrose preference, tail suspension, or Porsolt forced swim test. Mice did not display signs of learned helplessness (LH) when compared to sham. Accordingly, cluster analysis revealed only a slightly higher quota of LH in HF (38%) vs. sham mice (32%). But strikingly, three-group cluster analysis revealed an additional intermediate subpopulation at risk for LH after HF (29%). Interestingly, this population featured elevated cardiac expression of nr4a1. CONCLUSIONS: The LH paradigm uncovered a subtle predisposition to depressive-like behaviour after MI, whereas testing for anhedonia and despair was insufficient to show a behavioural shift in mice. Therefore, we suggest an accumulating risk profile and a multiple-hits hypothesis regarding the pathogenesis of co-morbid depression after MI. Symptoms of LH may present a marker of subclinical depression after MI, the impact of which remains to be investigated. The proposed sequence of behavioural testing enables the mechanistic dissection of cardio-psychogenic signalling in the future.


Assuntos
Depressão/etiologia , Insuficiência Cardíaca/etiologia , Desamparo Aprendido , Infarto do Miocárdio/complicações , Infarto do Miocárdio/psicologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Risco
10.
Sci Rep ; 8(1): 8097, 2018 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-29802307

RESUMO

TAR DNA-binding protein 43 (TDP-43) is a key player in neurodegenerative diseases including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Accumulation of TDP-43 is associated with neuronal death in the brain. How increased and disease-causing mutant forms of TDP-43 induce cell death remains unclear. Here we addressed the role of TDP-43 during neural development and show that reduced TDP-43 causes defects in neural stem/progenitor cell proliferation but not cell death. However, overexpression of wild type and TDP-43A315T proteins induce p53-dependent apoptosis of neural stem/progenitors and human induced pluripotent cell (iPS)-derived immature cortical neurons. We show that TDP-43 induces expression of the proapoptotic BH3-only genes Bbc3 and Bax, and that p53 inhibition rescues TDP-43 induced cell death of embryonic mouse, and human cortical neurons, including those derived from TDP-43G298S ALS patient iPS cells. Hence, an increase in wild type and mutant TDP-43 induces p53-dependent cell death in neural progenitors developing neurons and this can be rescued. These findings may have important implications for accumulated or mutant TDP-43 induced neurodegenerative diseases.


Assuntos
Apoptose , Proteínas de Ligação a DNA/metabolismo , Células-Tronco Neurais/citologia , Neurônios/citologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Ciclo Celular , Inibidor de Quinase Dependente de Ciclina p21/genética , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Camundongos , Mutação , Neurogênese , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
11.
FASEB J ; 32(6): 3005-3019, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29401591

RESUMO

Systemic corticosteroids have been the mainstay of treatment for various hearing disorders for more than 30 yr. Accordingly, numerous studies have described glucocorticoids (GCs) and stressors to be protective in the auditory organ against damage associated with a variety of health conditions, including noise exposure. Conversely, stressors are also predictive risk factors for hearing disorders. How both of these contrasting stress actions are linked has remained elusive. Here, we demonstrate that higher corticosterone levels during acoustic trauma in female rats is highly correlated with a decline of auditory fiber responses in high-frequency cochlear regions, and that hearing thresholds and the outer hair cell functions (distortion products of otoacoustic emissions) are left unaffected. Moreover, when GC receptor (GR) or mineralocorticoid receptor (MR) activation was antagonized by mifepristone or spironolactone, respectively, GR, but not MR, inhibition significantly and permanently attenuated trauma-induced effects on auditory fiber responses, including inner hair cell ribbon loss and related reductions of early and late auditory brainstem responses. These findings strongly imply that higher corticosterone stress levels profoundly impair auditory nerve processing, which may influence central auditory acuity. These changes are likely GR mediated as they are prevented by mifepristone.-Singer, W., Kasini, K., Manthey, M., Eckert, P., Armbruster, P., Vogt, M. A., Jaumann, M., Dotta, M., Yamahara, K., Harasztosi, C., Zimmermann, U., Knipper, M., Rüttiger, L. The glucocorticoid antagonist mifepristone attenuates sound-induced long-term deficits in auditory nerve response and central auditory processing in female rats.


Assuntos
Nervo Coclear/fisiopatologia , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Glucocorticoides/antagonistas & inibidores , Transtornos da Audição/fisiopatologia , Perda Auditiva Provocada por Ruído/fisiopatologia , Mifepristona/farmacologia , Animais , Cóclea/metabolismo , Cóclea/patologia , Cóclea/fisiopatologia , Nervo Coclear/metabolismo , Nervo Coclear/patologia , Feminino , Glucocorticoides/efeitos adversos , Glucocorticoides/farmacologia , Transtornos da Audição/induzido quimicamente , Transtornos da Audição/tratamento farmacológico , Transtornos da Audição/metabolismo , Perda Auditiva Provocada por Ruído/induzido quimicamente , Perda Auditiva Provocada por Ruído/tratamento farmacológico , Perda Auditiva Provocada por Ruído/metabolismo , Ratos , Ratos Wistar , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo
12.
Biochim Biophys Acta Biomembr ; 1860(4): 887-894, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29069569

RESUMO

The vestibule loop regions of aquaglyceroporins are involved in accumulation of glycerol inside the channel pore. Even though most loop regions do not show high sequence similarity among aquaglyceroporins, loop E is highly conserved in aquaglyceroporins, but not in members of the homologous aquaporins. Specifically, a tryptophan residue is extremely conserved within this loop. We have investigated the role of this residue (Trp219) that deeply protrudes into the protein and potentially interacts with adjacent loops, using the E. coli aqualgyeroporin GlpF as a model. Replacement of Trp219 affects the activity of GlpF and impairs the stability of the tetrameric protein. Furthermore, we have identified an amino acid cluster involving Trp219 that stabilizes the GlpF tetramer. Based on our results we propose that Trp219 is key for formation of a defined vestibule structure, which is crucial for glycerol accumulation as well as for the stability of the active GlpF tetramer.


Assuntos
Aminoácidos/metabolismo , Aquagliceroporinas/metabolismo , Aquaporinas/metabolismo , Proteínas de Escherichia coli/metabolismo , Triptofano/metabolismo , Aminoácidos/genética , Aquagliceroporinas/química , Aquagliceroporinas/genética , Aquaporinas/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Glicerol/metabolismo , Modelos Moleculares , Mutação , Conformação Proteica , Multimerização Proteica , Estabilidade Proteica , Triptofano/genética
13.
Behav Brain Res ; 335: 71-79, 2017 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-28782590

RESUMO

Genetically altered mice are available on different background strains. While respective backcrosses are often performed for pragmatic reasons, e.g. references, comparability, or existing protocols, the interaction between the mutations per se and the background strain often remains a neglected factor. The heterozygous mutation of the glucocorticoid receptor gene (GR) represents a well-examined model for depressive-like behavior in mice. To address the question in how far a robust depressive-like phenotype on a distinct background strain may allow a generalized conclusion, we analyzed respective phenotypes in two commonly used inbred strains: i.) C57BL/6N and ii.) BALB/c. Beside the use of different genetic models, we also extended our approach by applying two alternative paradigms to induce a depressive-like phenotype. Our study therefore comprised the model of 'unpredictable chronic mild stress' (UCMS) for four weeks and 'learned helplessness' (LH), which were used to study the role of GR, a key player in the development of depression. In the course of the experiment two cohorts of male GR+/- mice on either C57BL/6N or BALB/c background strain underwent a behavioral test battery to assess basal and depressive-like features. While both stress paradigms were functional in inducing depressive-like changes, the results were strictly strain-dependent. The genetic consequences became even more obvious under non-stress conditions with significant effects detected in BALB/c mice, which indicates a different basal stress predisposition due to differences in the genetic background.


Assuntos
Transtorno Depressivo/genética , Camundongos Endogâmicos/genética , Receptores de Glucocorticoides/genética , Animais , Comportamento Animal , Depressão/genética , Modelos Animais de Doenças , Genótipo , Desamparo Aprendido , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos/fisiologia , Fenótipo , Receptores de Glucocorticoides/metabolismo , Estresse Psicológico/genética
14.
J Neurochem ; 141(3): 461-471, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28266720

RESUMO

The p75 neurotrophin receptor (p75NTR) is a low-affinity receptor that is capable of binding neurotrophins. Two different p75NTR knockout mouse lines are available either with a deletion in Exon III (p75NTRExIII-/- ) or in Exon IV (p75NTRExIV-/- ). In p75NTRExIII knockout mice, only the full-length p75NTR is deleted, whereas in p75NTRExIV knockout mice, the full-length as well as the truncated isoform of the receptor is deleted. Deletion of p75NTR has been shown to affect, among others, the septohippocampal cholinergic innervation pattern and neuronal plasticity within the hippocampus. We hypothesize that deletion of p75NTR also alters the morphology and physiology of a further key structure of the limbic system, the amygdala. Our results indicate that deletion of p75NTR also increases cholinergic innervation in the basolateral amygdala in adult as well as aged p75NTRExIII-/- and p75NTRExIV-/- mice. The p75NTRExIV-/- mice did not display altered long-term potentiation (LTP) in the basolateral amygdala as compared to age-matched control littermates. However, p75NTRExIII-/- mice display stronger LTP in the basolateral amygdala compared to age-matched controls. Bath-application of K252a (a trk antagonist) did not inhibit the induction of LTP in the basolateral amygdala, but reduced the level of LTP in p75NTRExIII-/- mice to levels seen in respective controls. Moreover, p75NTRExIII-/- mice display altered behavior in the dark/light box. Thus, deletion of p75NTR in mice leads to physiological and morphological changes in the amygdala and altered behavior that is linked to the limbic system.


Assuntos
Tonsila do Cerebelo , Ansiedade/psicologia , Sistema Nervoso Parassimpático , Receptores de Fator de Crescimento Neural/deficiência , Tonsila do Cerebelo/química , Animais , Comportamento Animal , Química Encefálica/genética , Fibras Colinérgicas , Condicionamento Psicológico , Fenômenos Eletrofisiológicos , Éxons , Medo , Imuno-Histoquímica , Potenciação de Longa Duração , Camundongos , Camundongos Knockout , Sistema Nervoso Parassimpático/química , Receptores de Fator de Crescimento Neural/genética
15.
Neuropsychopharmacology ; 42(5): 1058-1069, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27905406

RESUMO

It has previously been shown that the inhibition of L-type calcium channels (LTCCs) decreases alcohol consumption, although the contribution of the central LTCC subtypes Cav1.2 and Cav1.3 remains unknown. Here, we determined changes in Cav1.2 (Cacna1c) and Cav1.3 (Cacna1d) mRNA and protein expression in alcohol-dependent rats during protracted abstinence and naive controls using in situ hybridization and western blot analysis. Functional validation was obtained by electrophysiological recordings of calcium currents in dissociated hippocampal pyramidal neurons. We then measured alcohol self-administration and cue-induced reinstatement of alcohol seeking in dependent and nondependent rats after intracerebroventricular (i.c.v.) injection of the LTCC antagonist verapamil, as well as in mice with an inducible knockout (KO) of Cav1.2 in Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα)-expressing neurons. Our results show that Cacna1c mRNA concentration was increased in the amygdala and hippocampus of alcohol-dependent rats after 21 days of abstinence, with no changes in Cacna1d mRNA. This was associated with increased Cav1.2 protein concentration and L-type calcium current amplitudes. Further analysis of Cacna1c mRNA in the CA1, basolateral amygdala (BLA), and central amygdala (CeA) revealed a dynamic regulation over time during the development of alcohol dependence. The inhibition of central LTCCs via i.c.v. administration of verapamil prevented cue-induced reinstatement of alcohol seeking in alcohol-dependent rats. Further studies in conditional Cav1.2-KO mice showed a lack of dependence-induced increase of alcohol-seeking behavior. Together, our data indicate that central Cav1.2 channels, rather than Cav1.3, mediate alcohol-seeking behavior. This finding may be of interest for the development of new antirelapse medications.


Assuntos
Alcoolismo/fisiopatologia , Canais de Cálcio Tipo L/fisiologia , Canais de Cálcio/fisiologia , Comportamento de Procura de Droga , Etanol/administração & dosagem , Alcoolismo/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Bloqueadores dos Canais de Cálcio/administração & dosagem , Canais de Cálcio/metabolismo , Canais de Cálcio Tipo L/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiologia , Masculino , Potenciais da Membrana/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , RNA Mensageiro , Ratos Wistar , Verapamil/administração & dosagem
16.
Cereb Cortex ; 26(10): 3991-4003, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27507786

RESUMO

A chromosomal microdeletion at the 22q11.2 locus is associated with extensive cognitive impairments, schizophrenia and other psychopathology in humans. Previous reports indicate that mouse models of the 22q11.2 microdeletion syndrome (22q11.2DS) may model the genetic basis of cognitive deficits relevant for neuropsychiatric disorders such as schizophrenia. To assess the models usefulness for drug discovery, a novel mouse (Df(h22q11)/+) was assessed in an extensive battery of cognitive assays by partners within the NEWMEDS collaboration (Innovative Medicines Initiative Grant Agreement No. 115008). This battery included classic and touchscreen-based paradigms with recognized sensitivity and multiple attempts at reproducing previously published findings in 22q11.2DS mouse models. This work represents one of the most comprehensive reports of cognitive functioning in a transgenic animal model. In accordance with previous reports, there were non-significant trends or marginal impairment in some tasks. However, the Df(h22q11)/+ mouse did not show comprehensive deficits; no robust impairment was observed following more than 17 experiments and 14 behavioral paradigms. Thus - within the current protocols - the 22q11.2DS mouse model fails to mimic the cognitive alterations observed in human 22q11.2 deletion carriers. We suggest that the 22q11.2DS model may induce liability for cognitive dysfunction with additional "hits" being required for phenotypic expression.


Assuntos
Cognição , Síndrome de DiGeorge/psicologia , Modelos Animais de Doenças , Camundongos Transgênicos , Animais , Atenção , Estudos de Coortes , Discriminação Psicológica , Descoberta de Drogas , Função Executiva , Feminino , Inibição Psicológica , Aprendizagem , Masculino , Memória , Camundongos Endogâmicos C57BL , Testes Neuropsicológicos , Fenótipo , Pesquisa Translacional Biomédica
17.
Horm Behav ; 81: 97-105, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27059527

RESUMO

The translational assessment of mechanisms underlying cognitive functions using touchscreen-based approaches for rodents is growing in popularity. In these paradigms, daily training is usually accompanied by extended food restriction to maintain animals' motivation to respond for rewards. Here, we show a transient elevation in stress hormone levels due to food restriction and touchscreen training, with subsequent adaptation effects, in fecal corticosterone metabolite concentrations, indicating effective coping in response to physical and psychological stressors. Corticosterone concentrations of experienced but training-deprived mice revealed a potential anticipation of task exposure, indicating a possible temporary environmental enrichment-like effect caused by cognitive challenge. Furthermore, the analyses of immediate early gene (IEG) immunoreactivity in the hippocampus revealed alterations in Arc, c-Fos and zif268 expression immediately following training. In addition, BDNF expression was altered as a function of satiation state during food restriction. These findings suggest that standard protocols for touchscreen-based training induce changes in hippocampal neuronal activity related to satiation and learning that should be considered when using this paradigm.


Assuntos
Glândulas Suprarrenais/metabolismo , Restrição Calórica/psicologia , Condicionamento Psicológico/fisiologia , Neurônios/metabolismo , Recompensa , Tato , Adaptação Psicológica/fisiologia , Animais , Restrição Calórica/veterinária , Corticosterona/metabolismo , Exposição Ambiental , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Condicionamento Físico Animal/fisiologia , Condicionamento Físico Animal/psicologia , RNA Mensageiro/metabolismo
18.
Int J Dev Neurosci ; 50: 55-64, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26970009

RESUMO

Fibroblast growth factor 2 (FGF-2) is an abundant growth factor in the brain and exerts multiple functions on neural cells ranging from cell division, cell fate determination to differentiation. However, many details of the molecular mechanisms underlying the diverse functions of FGF-2 are poorly understood. In a comparative microarray analysis of motor sensory cortex (MSC) tissue of adult knockout (FGF-2(-/-)) and control (FGF-2(+/+)) mice, we found a substantial number of regulated genes, which are implicated in cytoskeletal machinery dynamics. Specifically, we found a prominent downregulation of Arhgef6. Arhgef6 mRNA was significantly reduced in the FGF-2(-/-) cortex, and Arhgef6 protein virtually absent, while RhoA protein levels were massively increased and Cdc42 protein levels were reduced. Since Arhgef6 is localized to dendritic spines, we next analyzed dendritic spines of adult FGF2(-/-) and control mouse cortices. Spine densities were significantly increased, whereas mean length of spines on dendrites of layer V of MSC neurons in adult FGF-2(-/-) mice was significantly decreased as compared to respective controls. Furthermore, neurite length in dissociated cortical cultures from E18 FGF-2(-/-) mice was significantly reduced at DIV7 as compared to wildtype neurons. Despite the fact that altered neuronal morphology and alterations in dendritic spines were observed, FGF-2(-/-) mice behave relatively unsuspicious in several behavioral tasks. However, FGF-2(-/-) mice exhibited decreased thermal pain sensitivity in the hotplate-test.


Assuntos
Espinhas Dendríticas/genética , Regulação para Baixo/genética , Fator 2 de Crescimento de Fibroblastos/deficiência , Crescimento Neuronal/genética , Neurônios/citologia , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo , Adaptação Ocular/genética , Animais , Células Cultivadas , Córtex Cerebral/citologia , Embrião de Mamíferos , Fator 2 de Crescimento de Fibroblastos/genética , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Neuritos/fisiologia , Fosfopiruvato Hidratase/metabolismo , Tempo de Reação/genética , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Natação/psicologia , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteínas rho de Ligação ao GTP/genética , Proteínas rho de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismo
19.
Eur Arch Psychiatry Clin Neurosci ; 266(7): 673-7, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26482736

RESUMO

NMDA receptor (NMDAR) antagonists induce in perinatal rodent cortical apoptosis and protracted schizophrenia-like alterations ameliorated by antipsychotic treatment. The broad-spectrum antibiotic minocycline elicits antipsychotic and neuroprotective effects. Here we tested, if minocycline protects also against apoptosis triggered by the NMDAR antagonist MK-801 at postnatal day 7. Surprisingly, minocycline induced widespread cortical apoptosis and exacerbated MK-801-triggered cell death. In some areas such as the subiculum, the pro-apoptotic effect of minocycline was even more pronounced than that elicited by MK-801. These data reveal among antipsychotics unique pro-apoptotic properties of minocycline, raising concerns regarding consequences for brain development and the use in children.


Assuntos
Antibacterianos/farmacologia , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Minociclina/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Antibacterianos/administração & dosagem , Encéfalo/patologia , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Minociclina/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem
20.
Cell Mol Neurobiol ; 36(7): 1215-8, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26645823

RESUMO

The recently identified Cystine-knot containing AMPAR-associated protein (Ckamp44) represents a novel AMPAR-related protein that critically controls AMPAR-mediated currents and short-term plasticity. However, the effects of the lack of this protein at network level are not entirely understood. Here we used c-Fos brain mapping to analyse whether the excitatory/inhibitory balance is altered in the absence of the Ckamp44. We found that Ckamp44(-/-) mice treated with an NMDAR antagonist exhibited a very robust c-Fos expression pattern, similar with that seen in mice lacking the GluN2A subunit of NMDAR treated with the same compound. This finding is unexpected, in particular, since Ckamp44 expression is strongest in dentate gyrus granule cells and less abundant in the rest of the brain.


Assuntos
Hipocampo/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Plasticidade Neuronal/fisiologia , Receptores de AMPA/metabolismo , Sinapses/metabolismo , Animais , Genes fos/fisiologia , Camundongos , Receptores de N-Metil-D-Aspartato/metabolismo , Transmissão Sináptica/fisiologia
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