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1.
Cereb Cortex ; 30(4): 2627-2641, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-31800024

RESUMO

Numerous studies provide increasing evidence, which supports the ideas that every cell in the brain of males may differ from those in females due to differences in sex chromosome complement as well as in response to hormonal effects. In this study, we address the question as to whether actions of neurosteroids, thus steroids, which are synthesized and function within the brain, contribute to sex-specific hippocampal synaptic plasticity. We have previously shown that predominantly in the female hippocampus, does inhibition of the conversion of testosterone to estradiol affect synaptic transmission. In this study, we show that testosterone and its metabolite dihydrotestosterone are essential for hippocampal synaptic transmission specifically in males. This also holds true for the density of mushroom spines and of spine synapses. We obtained similar sex-dependent results using primary hippocampal cultures of male and female animals. Since these cultures originated from perinatal animals, our findings argue for sex-dependent differentiation of hippocampal neurons regarding their responsiveness to sex neurosteroids up to birth, which persist during adulthood. Hence, our in vitro findings may point to a developmental effect either directly induced by sex chromosomes or indirectly by fetal testosterone secretion during the perinatal critical period, when developmental sexual priming takes place.


Assuntos
Hipocampo/metabolismo , Plasticidade Neuronal/fisiologia , Neuroesteroides/metabolismo , Caracteres Sexuais , Sinapses/metabolismo , Animais , Células Cultivadas , Feminino , Hipocampo/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Cultura de Órgãos , Ratos , Ratos Wistar , Sinapses/ultraestrutura
2.
Cereb Cortex ; 30(3): 1688-1707, 2020 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-31667489

RESUMO

Reelin is an extracellular matrix protein, known for its dual role in neuronal migration during brain development and in synaptic plasticity at adult stages. During the perinatal phase, Reelin expression switches from Cajal-Retzius (CR) cells, its main source before birth, to inhibitory interneurons (IN), the main source of Reelin in the adult forebrain. IN-derived Reelin has been associated with schizophrenia and temporal lobe epilepsy; however, the functional role of Reelin from INs is presently unclear. In this study, we used conditional knockout mice, which lack Reelin expression specifically in inhibitory INs, leading to a substantial reduction in total Reelin expression in the neocortex and dentate gyrus. Our results show that IN-specific Reelin knockout mice exhibit normal neuronal layering and normal behavior, including spatial reference memory. Although INs are the major source of Reelin within the adult stem cell niche, Reelin from INs does not contribute substantially to normal adult neurogenesis. While a closer look at the dentate gyrus revealed some unexpected alterations at the cellular level, including an increase in the number of Reelin expressing CR cells, overall our data suggest that Reelin derived from INs is less critical for cortex development and function than Reelin expressed by CR cells.


Assuntos
Moléculas de Adesão Celular Neuronais/metabolismo , Giro Denteado/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Interneurônios/metabolismo , Neocórtex/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Serina Endopeptidases/metabolismo , Animais , Comportamento Animal/fisiologia , Movimento Celular/fisiologia , Giro Denteado/fisiopatologia , Hipocampo/metabolismo , Interneurônios/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurogênese/fisiologia , Neurônios/metabolismo , Folhas de Planta/metabolismo , Proteína Reelina
3.
Eur J Neurosci ; 52(1): 2548-2559, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31403726

RESUMO

Sex-dependent differences in learning and memory formation in humans have been frequently shown. The mechanisms underlying the formation and retention of memories are assumed to involve synaptic plasticity in the hippocampus. Estradiol was shown to effect synaptic plasticity in the hippocampus of rodents. The effects after exogenous application of estradiol to animals frequently produce inconsistent results, in particular, if sex is not considered in the studies. Recently we provided evidence that locally synthesized estradiol plays an essential role on synaptic connectivity in the hippocampus of females but not of male mice. In females, inhibition of local estradiol synthesis leads to synapse loss, which results from impairment of long-term potentiation and dephosphorylation of cofilin, and thereby the destabilization of postsynaptic dendritic spines. This sex-dependency was also seen in the classical aromatase knock-out mouse. Intriguingly, no differences between sexes have been found in a conditional forebrain-specific aromatase knock-out mouse. Altogether, the findings underscore the necessity of including 'Sex as a Biological Variable' in studies of sex steroid-induced synaptic plasticity.


Assuntos
Aromatase , Estradiol , Animais , Aromatase/metabolismo , Espinhas Dendríticas/metabolismo , Estradiol/farmacologia , Estrogênios , Feminino , Hipocampo/metabolismo , Masculino , Camundongos , Plasticidade Neuronal , Roedores/metabolismo
4.
J Am Soc Nephrol ; 30(5): 824-839, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30971456

RESUMO

BACKGROUND: About 3%-5% of adults with membranous nephropathy have autoantibodies directed against thrombospondin type 1 domain-containing 7A (THSD7A), a podocyte-expressed transmembrane protein. However, the temporal and spatial expression of THSD7A and its biologic function for podocytes are unknown, information that is needed to understand the effects of THSD7A autoantibodies in this disease. METHODS: Using a variety of microscopic techniques, we analyzed THSD7A localization in postnatal, adult, and autoantibody-injected mice as well as in human podocytes. We also analyzed THSD7A function in human podocytes using confocal microscopy; Western blotting; and adhesion and migration assays. RESULTS: We found that THSD7A expression begins on glomerular vascularization with slit diaphragm formation in development. THSD7A localizes to the basal aspect of foot processes, closely following the meanders of the slit diaphragm in human and mice. Autoantibodies binding to THSD7A localize to the slit diaphragm. In human podocytes, THSD7A expression is accentuated at filopodia and thin arborized protrusions, an expression pattern associated with decreased membrane activity of cytoskeletal regulators. We also found that, phenotypically, THSD7A expression in human podocytes is associated not only with increases in cell size, enhanced adhesion, and reduced detachment from collagen type IV-coated plates but also, with decreased ability to migrate. CONCLUSIONS: Our findings suggest that THSD7A functions as a foot process protein involved in the stabilization of the slit diaphragm of mature podocytes and that autoantibodies to THSD7A, on the basis of their localization, might structurally and functionally alter the slit diaphragm's permeability to protein.


Assuntos
Antígenos de Superfície/genética , Glomerulonefrite Membranosa/genética , Glomérulos Renais/metabolismo , Proteínas de Membrana/metabolismo , Trombospondinas/imunologia , Animais , Antígenos de Superfície/imunologia , Autoanticorpos/imunologia , Western Blotting , Células Cultivadas , Regulação da Expressão Gênica , Taxa de Filtração Glomerular , Glomerulonefrite Membranosa/fisiopatologia , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Podócitos/imunologia , Proteinúria/metabolismo , Sensibilidade e Especificidade , Trombospondinas/metabolismo
5.
J Neurochem ; 150(2): 173-187, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30790293

RESUMO

Clinical and animal studies have revealed sex-specific differences in histopathological and neurological outcome after traumatic brain injury (TBI). The impact of perioperative administration of sex steroid inhibitors on TBI is still elusive. Here, we subjected male and female C57Bl/6N mice to the controlled cortical impact (CCI) model of TBI and applied pharmacological inhibitors of steroid hormone synthesis, that is, letrozole (LET, inhibiting estradiol synthesis by aromatase) and finasteride (FIN, inhibiting dihydrotestosterone synthesis by 5α-reductase), respectively, starting 72 h prior CCI, and continuing for a further 48 h after CCI. Initial gene expression analyses showed that androgen (Ar) and estrogen receptors (Esr1) were sex-specifically altered 72 h after CCI. When examining brain lesion size, we found larger lesions in male than in female mice, but did not observe effects of FIN or LET treatment. However, LET treatment exacerbated neurological deficits 24 and 72 h after CCI. On the molecular level, FIN administration reduced calpain-dependent spectrin breakdown products, a proxy of excitotoxicity and disturbed Ca2+ homeostasis, specifically in males, whereas LET increased the reactive astrocyte marker glial fibrillary acid protein specifically in females. Examination of neurotrophins (brain-derived neurotrophic factor, neuronal growth factor, NT-3) and their receptors (p75NTR , TrkA, TrkB, TrkC) revealed CCI-induced down-regulation of TrkB and TrkC protein expression, which was reduced by LET in both sexes. Interestingly, FIN decreased neuronal growth factor mRNA expression and protein levels of its receptor TrkA only in males. Taken together, our data suggest a sex-specific impact on pathogenic processes in the injured brain after TBI. Sex hormones may thus modulate pathogenic processes in experimental TBI.


Assuntos
Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Encéfalo/efeitos dos fármacos , Di-Hidrotestosterona/antagonistas & inibidores , Estradiol/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Antagonistas de Estrogênios/farmacologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Crescimento Neural/efeitos dos fármacos , Caracteres Sexuais
6.
Hippocampus ; 29(6): 550-565, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30394609

RESUMO

Cajal-Retzius (CR) cells are early-born glutamatergic neurons that are primarily known as the early main source of the signal protein Reelin. In the reeler mutant, the absence of Reelin causes severe defects in the radial migration of neurons, resulting in abnormal cortical layering. To date, the exact morphological properties of CR-cells independent of Reelin are unknown. With this in view, we studied the ontogenesis, density, and distribution of CR-cells in reeler mice that were cross-bred with a CXCR4-EGFP reporter mouse line, thus enabling us to clearly identify CR-cells positions in the disorganized hippocampus of the reeler mouse. As evidenced by morphological analysis, differences were found regarding CR-cell distribution and density: generally, we found fewer CR-cells in the developing and adult reeler hippocampus as compared to the hippocampus of wild-type animals (WT); however, in reeler mice, CR-cells were much more closely associated to the hippocampal fissure (HF), resulting in relatively higher local CR-cell densities. This higher local cell density was accompanied by stronger immunoreactivity of the CXCR4 ligand, stroma-derived factor-1 (SDF-1) that is known to regulate CR-cell positioning. Importantly, confocal microscopy indicates an integration of CR-cells into the developing and adult hippocampal network in reeler mice, raising evidence that network integration of CR-cells might be independent of Reelin.


Assuntos
Moléculas de Adesão Celular Neuronais/deficiência , Moléculas de Adesão Celular Neuronais/genética , Proteínas da Matriz Extracelular/deficiência , Proteínas da Matriz Extracelular/genética , Hipocampo/patologia , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Neurônios/patologia , Serina Endopeptidases/deficiência , Serina Endopeptidases/genética , Animais , Contagem de Células , Movimento Celular , Quimiocina CXCL12/metabolismo , Giro Denteado/metabolismo , Giro Denteado/patologia , Ácido Glutâmico/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Camundongos , Camundongos Mutantes Neurológicos , Camundongos Transgênicos , Microscopia Confocal , Rede Nervosa/metabolismo , Rede Nervosa/patologia , Neurogênese , Neurônios/metabolismo , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Proteína Reelina , Transdução de Sinais
7.
Cereb Cortex ; 28(2): 672-687, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28637318

RESUMO

In contrast to their near-disappearance in the adult neocortex, Cajal-Retzius cells have been suggested to persist longer in the hippocampus. A distinctive feature of the mature hippocampus, not maintained by other cortical areas, is its ability to sustain adult neurogenesis. Here, we have investigated whether environmental manipulations affecting hippocampal postnatal neurogenesis have a parallel impact on Cajal-Retzius cells. We used multiple mouse reporter lines to unequivocally identify Cajal-Retzius cells and quantify their densities during postnatal development. We found that exposure to an enriched environment increased the persistence of Cajal-Retzius cells in the hippocampus, but not in adjacent cortical regions. We did not observe a similar effect for parvalbumin-expressing interneurons, which suggested the occurrence of a cell type-specific process. In addition, we did not detect obvious changes either in Cajal-Retzius cell electrophysiological or morphological features, when compared with what previously reported in animals not exposed to enriched conditions. However, optogenetically triggered synaptic output of Cajal-Retzius cells onto local interneurons was enhanced, consistent with our observation of higher Cajal-Retzius cell densities. In conclusion, our data reveal a novel form of hippocampal, cell type-specific, experience-dependent network plasticity. We propose that this phenomenon may be involved in the regulation of enrichment-dependent enhanced hippocampal postnatal neurogenesis.


Assuntos
Meio Ambiente , Hipocampo/fisiologia , Células Intersticiais de Cajal/fisiologia , Rede Nervosa/fisiologia , Neurogênese/fisiologia , Neurônios/fisiologia , Fatores Etários , Animais , Feminino , Hipocampo/química , Hipocampo/citologia , Células Intersticiais de Cajal/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Rede Nervosa/química , Rede Nervosa/citologia , Neurônios/química
8.
J Neurosci ; 37(6): 1532-1545, 2017 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-28028198

RESUMO

The basolateral amygdala (BLA) integrates sensory input from cortical and subcortical regions, a function that requires marked synaptic plasticity. Here we provide evidence that cytochrome P450 aromatase (AROM), the enzyme converting testosterone to 17ß-estradiol (E2), contributes to the regulation of this plasticity in a sex-specific manner. We show that AROM is expressed in the BLA, particularly in the basolateral nucleus (BL), in male and female rodents. Systemic administration of the AROM inhibitor letrozole reduced spine synapse density in the BL of adult female mice but not in the BL of male mice. Similarly, in organotypic corticoamygdalar slice cultures from immature rats, treatment with letrozole significantly reduced spine synapses in the BL only in cultures derived from females. In addition, letrozole sex-specifically altered synaptic properties in the BL: in acute slices from juvenile (prepubertal) female rats, wash-in of letrozole virtually abolished long-term potentiation (LTP), whereas it did not prevent the generation of LTP in the slices from males. Together, these data indicate that neuron-derived E2 modulates synaptic plasticity in rodent BLA sex-dependently. As protein expression levels of AROM, estrogen and androgen receptors did not differ between males and females and were not sex-specifically altered by letrozole, the findings suggest sex-specific mechanisms of E2 signaling.SIGNIFICANCE STATEMENT The basolateral amygdala (BLA) is a key structure of the fear circuit. This research reveals a sexually dimorphic regulation of synaptic plasticity in the BLA involving neuronal aromatase, which produces the neurosteroid 17ß-estradiol (E2). As male and female neurons in rodent BLA responded differently to aromatase inhibition both in vivo and in vitro, our findings suggest that E2 signaling in BLA neurons is regulated sex-dependently, presumably via mechanisms that have been established during sexual determination. These findings could be relevant for the understanding of sex differences in mood disorders and of the side effects of cytochrome P450 aromatase inhibitors, which are frequently used for breast cancer therapy.


Assuntos
Inibidores da Aromatase/farmacologia , Aromatase/fisiologia , Complexo Nuclear Basolateral da Amígdala/fisiologia , Plasticidade Neuronal/fisiologia , Caracteres Sexuais , Animais , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Letrozol , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Nitrilas/farmacologia , Técnicas de Cultura de Órgãos , Ratos , Triazóis/farmacologia
9.
Learn Mem ; 24(12): 650-659, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29142062

RESUMO

The serine protease inhibitor neuroserpin regulates the activity of tissue-type plasminogen activator (tPA) in the nervous system. Neuroserpin expression is particularly prominent at late stages of neuronal development in most regions of the central nervous system (CNS), whereas it is restricted to regions related to learning and memory in the adult brain. The physiological expression pattern of neuroserpin, its high degree of colocalization with tPA within the CNS, together with its dysregulation in neuropsychiatric disorders, suggest a role in formation and refinement of synapses. In fact, studies in cell culture and mice point to a role for neuroserpin in dendritic branching, spine morphology, and modulation of behavior. In this study, we investigated the physiological role of neuroserpin in the regulation of synaptic density, synaptic plasticity, and behavior in neuroserpin-deficient mice. In the absence of neuroserpin, mice show a significant decrease in spine-synapse density in the CA1 region of the hippocampus, while expression of the key postsynaptic scaffold protein PSD-95 is increased in this region. Neuroserpin-deficient mice show decreased synaptic potentiation, as indicated by reduced long-term potentiation (LTP), whereas presynaptic paired-pulse facilitation (PPF) is unaffected. Consistent with altered synaptic plasticity, neuroserpin-deficient mice exhibit cognitive and sociability deficits in behavioral assays. However, although synaptic dysfunction is implicated in neuropsychiatric disorders, we do not detect alterations in expression of neuroserpin in fusiform gyrus of autism patients or in dorsolateral prefrontal cortex of schizophrenia patients. Our results identify neuroserpin as a modulator of synaptic plasticity, and point to a role for neuroserpin in learning and memory.


Assuntos
Regulação da Expressão Gênica/genética , Plasticidade Neuronal/genética , Neuropeptídeos/deficiência , Inibidores de Serina Proteinase/metabolismo , Serpinas/deficiência , Comportamento Social , Sinapses/genética , Adolescente , Adulto , Animais , Transtorno Autístico/genética , Transtorno Autístico/patologia , Transtorno Autístico/psicologia , Criança , Comportamento Exploratório/fisiologia , Hipocampo/fisiologia , Hipocampo/ultraestrutura , Humanos , Potenciação de Longa Duração/genética , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Neuropeptídeos/genética , Serpinas/genética , Sinapses/fisiologia , Sinapses/ultraestrutura , Proteína 25 Associada a Sinaptossoma/metabolismo , Adulto Jovem , Neuroserpina
10.
J Neurochem ; 140(1): 126-139, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27861893

RESUMO

Locally synthesized estradiol plays an important role in synaptic plasticity in the hippocampus. We have previously shown that in hippocampal neurons, activity of the enzyme aromatase, which converts testosterone into estradiol, is reduced via Ca2+ -dependent phosphorylation. Synaptopodin is a highly estrogen responsive protein, and it has been shown that it is an important regulator of synaptic plasticity, mediated by its close association with internal calcium stores. In this study, we show that the expression of synaptopodin is stronger in the hippocampus of female animals than in that of male animals. Phosphorylation of aromatase, using letrozole, however, down-regulates synaptopodin immunohistochemistry in the hippocampus of both male and females. Similarly, in aromatase knock-out mice synaptopodin expression in the hippocampus is reduced sex independently. Using primary-dissociated hippocampal neurons, we found that evoked release of Ca2+ from internal stores down-regulates aromatase activity, which is paralleled by reduced expression of synaptopodin. Opposite effects were achieved after inhibition of the release. Calcium-dependent regulation of synaptopodin expression was abolished when the control of aromatase activity by the Ca2+ transients was disrupted. Our data suggest that the regulation of aromatase activity by Ca2+ transients in neurons contributes to synaptic plasticity in the hippocampus of male and female animals as an on-site regulatory mechanism.


Assuntos
Inibidores da Aromatase/farmacologia , Aromatase/metabolismo , Proteínas dos Microfilamentos/fisiologia , Animais , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/fisiologia , Células Cultivadas , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Letrozol , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nitrilas/farmacologia , Ratos , Ratos Wistar , Triazóis/farmacologia
11.
Hum Mol Genet ; 24(4): 1007-18, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25296915

RESUMO

In humans, lack of phenylalanine hydroxylase (Pah) activity results in phenylketonuria (PKU), which is associated with the development of severe mental retardation after birth. The underlying mechanisms, however, are poorly understood. Mutations of the Pah gene in Pah(enu2)/c57bl6 mice result in elevated levels of phenylalanine in serum similar to those in humans suffering from PKU. In our study, long-term potentiation (LTP) and paired-pulse facilitation, measured at CA3-CA1 Schaffer collateral synapses, were impaired in acute hippocampal slices of Pah(enu2)/c57bl6 mice. In addition, we found reduced expression of presynaptic proteins, such as synaptophysin and the synaptosomal-associated protein 25 (SNAP-25), and enhanced expression of postsynaptic marker proteins, such as synaptopodin and spinophilin. Stereological counting of spine synapses at the ultrastructural level revealed higher synaptic density in the hippocampus, commencing at 3 weeks and persisting up to 12 weeks after birth. Consistent effects were seen in response to phenylalanine treatment in cultures of dissociated hippocampal neurones. Most importantly, in the hippocampus of Pah(enu2)/c57bl6 mice, we found a significant reduction in microglia activity. Reorganization of hippocampal circuitry after birth, namely synaptic pruning, relies on elimination of weak synapses by activated microglia in response to neuronal activity. Hence, our data strongly suggest that reduced microglial activity in response to impaired synaptic transmission affects physiological postnatal remodelling of synapses in the hippocampus and may trigger the development of mental retardation in PKU patients after birth.


Assuntos
Hipocampo/metabolismo , Fenilcetonúrias/metabolismo , Transmissão Sináptica , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Humanos , Potenciação de Longa Duração , Camundongos , Camundongos Knockout , Microglia/metabolismo , Neurônios/metabolismo , Fenilalanina/farmacologia , Fenilalanina Hidroxilase/genética , Fenilcetonúrias/genética , Sinapses/metabolismo , Proteína 25 Associada a Sinaptossoma/genética , Proteína 25 Associada a Sinaptossoma/metabolismo
12.
Neural Plast ; 2016: 9802086, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27298742

RESUMO

Numerous studies show that 17ß-estradiol (E2) protects against Alzheimer's disease (AD) induced neurodegeneration. The E2-synthesizing enzyme aromatase is expressed in healthy hippocampi, but although the hippocampus is severely affected in AD, little is known about the expression of hippocampal aromatase in AD. To better understand the role of hippocampal aromatase in AD, we studied its expression in postmortem material from patients with AD and in a mouse model for AD (5xFAD mice). In human hippocampi, aromatase-immunoreactivity was observed in the vast majority of principal neurons and signal quantification revealed higher expression of aromatase protein in AD patients compared to age- and sex-matched controls. The tissue-specific first exons of aromatase I.f, PII, I.3, and I.6 were detected in hippocampi of controls and AD patients by RT-PCR. In contrast, 3-month-old, female 5xFAD mice showed lower expression of aromatase mRNA and protein (measured by qRT-PCR and semiquantitative immunohistochemistry) than WT controls; no such differences were observed in male mice. Our findings stress the importance of hippocampal aromatase expression in neurodegenerative diseases.


Assuntos
Doença de Alzheimer/enzimologia , Aromatase/biossíntese , Regulação Enzimológica da Expressão Gênica , Hipocampo/enzimologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Aromatase/genética , Feminino , Hipocampo/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade
13.
Hum Mol Genet ; 21(2): 268-86, 2012 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-21989057

RESUMO

Mutations in the ARHGEF6 gene, encoding the guanine nucleotide exchange factor αPIX/Cool-2 for the Rho GTPases Rac1 and Cdc42, cause X-linked intellectual disability (ID) in humans. We show here that αPix/Arhgef6 is primarily expressed in neuropil regions of the hippocampus. To study the role of αPix/Arhgef6 in neuronal development and plasticity and gain insight into the pathogenic mechanisms underlying ID, we generated αPix/Arhgef6-deficient mice. Gross brain structure in these mice appeared to be normal; however, analysis of Golgi-Cox-stained pyramidal neurons revealed an increase in both dendritic length and spine density in the hippocampus, accompanied by an overall loss in spine synapses. Early-phase long-term potentiation was reduced and long-term depression was increased in the CA1 hippocampal area of αPix/Arhgef6-deficient animals. Knockout animals exhibited impaired spatial and complex learning and less behavioral control in mildly stressful situations, suggesting that this model mimics the human ID phenotype. The structural and electrophysiological alterations in the hippocampus were accompanied by a significant reduction in active Rac1 and Cdc42, but not RhoA. In conclusion, we suggest that imbalance in activity of different Rho GTPases may underlie altered neuronal connectivity and impaired synaptic function and cognition in αPix/Arhgef6 knockout mice.


Assuntos
Transtornos Cognitivos/genética , Modelos Animais de Doenças , Doenças Genéticas Ligadas ao Cromossomo X/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Deficiência Intelectual/genética , Plasticidade Neuronal/genética , Proteínas rho de Ligação ao GTP/metabolismo , Animais , Aprendizagem em Labirinto , Camundongos , Camundongos Knockout , Fatores de Troca de Nucleotídeo Guanina Rho
15.
J Neurosci ; 32(24): 8116-26, 2012 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-22699893

RESUMO

Inhibitors of aromatase, the final enzyme of estradiol synthesis, are suspected of inducing memory deficits in women. In previous experiments, we found hippocampal spine synapse loss in female mice that had been treated with letrozole, a potent aromatase inhibitor. In this study, we therefore focused on the effects of letrozole on long-term potentiation (LTP), which is an electrophysiological parameter of memory and is known to induce spines, and on phosphorylation of cofilin, which stabilizes the spine cytoskeleton and is required for LTP in mice. In acute slices of letrozole-treated female mice with reduced estradiol serum concentrations, impairment of LTP started as early as after 6 h of treatment and progressed further, together with dephosphorylation of cofilin in the same slices. Theta-burst stimulation failed to induce LTP after 1 week of treatment. Impairment of LTP was followed by spine and spine synapse loss. The effects were confirmed in vitro by using hippocampal slice cultures of female mice. The sequence of effects in response to letrozole were similar in ovariectomized female and male mice, with, however, differences as to the degree of downregulation. Our data strongly suggest that impairment of LTP, followed by loss of mushroom spines and spine synapses in females, may have implications for memory deficits in women treated with letrozole.


Assuntos
Inibidores da Aromatase/farmacologia , Aromatase/fisiologia , Potenciação de Longa Duração/fisiologia , Nitrilas/farmacologia , Caracteres Sexuais , Triazóis/farmacologia , Animais , Células Cultivadas , Cofilina 1/metabolismo , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/ultraestrutura , Estradiol/sangue , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Letrozol , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Wistar , Sinapses/efeitos dos fármacos , Sinapses/fisiologia , Sinapses/ultraestrutura
16.
Hippocampus ; 23(2): 117-21, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22887836

RESUMO

The neurosteroid 17-beta estradiol (E2) plays an important role in neuronal plasticity, neurogenesis and neuroprotection of hippocampal neurons in slice cultures and the female brain. While some effects of E2 on hippocampal neurons observed in females were also seen in the male hippocampus, others seem to be specific to females. The current study aimed to further explore the effect of E2 on the male hippocampus by investigating the relationship between genetic variations in E2 synthesis and hippocampal gray matter (GM) volume. We chose a single nucleotide polymorphism (rs700158, SNP) in the gene CYP19A1 coding for the final enzyme (aromatase) in E2 synthesis. Men homozygous for the A allele of rs700518 have repeatedly been shown to have higher E2 serum levels than male carriers of the G allele. Two independent cohorts of healthy young men were genotyped for rs700518 and voxel-based morphometry (VBM) was performed on structural magnetic resonance images to determine genotype dependent group differences. Men homozygous for the A allele of rs700518 had greater bilateral posterior hippocampal GM volumes in both cohorts. Thus, the genotype associated with higher E2 serum levels was also associated with greater hippocampal gray matter.


Assuntos
Aromatase/genética , Estradiol/sangue , Variação Genética , Hipocampo/anatomia & histologia , Adolescente , Adulto , Estradiol/genética , Genótipo , Humanos , Interpretação de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto Jovem
17.
Psychoneuroendocrinology ; 156: 106320, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37307791

RESUMO

In order to translate the findings from the vast animal literature on the effect of 17ß-estradiol (E2) on brain and behavior to humans, a placebo-controlled pharmacological enhancement of E2 levels for at least 24 h is necessary. However, an exogenous increase in E2 for such a prolonged period might affect the endogenous secretion of other (neuroactive) hormones. Such effects would be of relevance for the interpretation of the effects of this pharmacological regimen on cognition and its neural correlates as well as be of basic scientific interest. We therefore administered a double dose of 12 mg of estradiol-valerate (E2V) to men and of 8 mg to naturally cycling women in their low-hormone phase, and assessed the concentration of two steroids critical to hormone regulation: follicle stimulating hormone (FSH) and luteinizing hormone (LH). We also assessed any changes in concentration of the neuroactive hormones progesterone (P4), testosterone (TST), dihydrotestosterone (DHT) and immune-like growth factor 1 (IGF-1). This regimen resulted in similar E2 levels in both sexes (saliva and serum). FSH and LH levels in both sexes were down-regulated to the same degree. P4 concentration decreased in both sexes only in serum but not saliva. TST and DHT levels dropped only in men whereas sex-hormone binding globulin was not affected. Finally, the concentration of IGF-1 decreased in both sexes. Based on previous studies on the effects of these neuroactive hormones, only the degree of downregulation of TST and DHT levels in men might have an impact on brain and behavior, which should be considered when interpreting the effects of the presented E2V regimes.


Assuntos
Fator de Crescimento Insulin-Like I , Hormônio Luteinizante , Masculino , Animais , Humanos , Feminino , Estradiol/farmacologia , Hormônio Foliculoestimulante , Testosterona/farmacologia , Menopausa , Valeratos
18.
J Neuroendocrinol ; 35(5): e13276, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37170708

RESUMO

Microglia have been shown to sculpt postnatal circuitry from birth up to adulthood due to their role in both synapse formation, synaptic pruning, and the elimination of weak, redundant synapses. Microglia are differentiated in a sex-dependent manner. In this study, we tested whether sexual differentiation of microglia results in sex-dependent postnatal reorganization of CA1 synaptic connectivity in the hippocampus. The stereological counting of synapses in mice using electron microscopy showed a continuous rise in synapse density until the fourth week, followed by a plateau phase and loss of synapses from the eighth week onwards, with no difference between sexes. This course of alteration in synapse numbers did not differ between sexes. However, selectively, on postnatal day (P) 14 the density of synapses was significantly higher in the female than in the male hippocampus. Higher synapse density in females was paralleled by higher activity of microglia, as indicated by morphological changes, CD68 expression, and proximity of microglia to synaptic sites. In Thy1-GFP mice, consistent with increased synapse numbers, bouton density was also clearly increased in females at P14. At this time point, CD47 expression, the "don't eat me" signal of neurons, was similar in males and females. The decrease in bouton density thereafter in conjunction with increased synapse numbers argues for a role of microglia in the formation of multispine boutons (MSB). Our data in females at P14 support the regulatory role of microglia in synapse density. Sexual differentiation of microglia, however, does not substantially affect long-term synaptic reorganization in the hippocampus.


Assuntos
Hipocampo , Microglia , Camundongos , Masculino , Feminino , Animais , Microglia/metabolismo , Neurônios , Sinapses/metabolismo , Terminações Pré-Sinápticas
19.
J Endocrinol ; 258(3)2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37399525

RESUMO

Estrogens regulate synaptic properties and influence hippocampus-related learning and memory via estrogen receptors, which include the G-protein-coupled estrogen receptor 1 (GPER1). Studying mice, in which the GPER1 gene is dysfunctional (GPER1-KO), we here provide evidence for sex-specific roles of GPER1 in these processes. GPER1-KO males showed reduced anxiety in the elevated plus maze, whereas the fear response ('freezing') was specifically increased in GPER1-KO females in a contextual fear conditioning paradigm. In the Morris water maze, spatial learning and memory consolidation was impaired by GPER1 deficiency in both sexes. Notably, in the females, spatial learning deficits and the fear response were more pronounced if mice were in a stage of the estrous cycle, in which E2 serum levels are high (proestrus) or rising (diestrus). On the physiological level, excitability at Schaffer collateral synapses in CA1 increased in GPER1-deficient males and in proestrus/diestrus ('E2 high') females, concordant with an increased hippocampal expression of the AMPA-receptor subunit GluA1 in GPER1-KO males and females as compared to wildtype males. Further changes included an augmented early long-term potentiation (E-LTP) maintenance specifically in GPER1-KO females and an increased hippocampal expression of spinophilin in metestrus/estrus ('E2 low') GPER1-KO females. Our findings suggest modulatory and sex-specific functions of GPER1 in the hippocampal network, which reduce rather than increase neuronal excitability. Dysregulation of these functions may underlie sex-specific cognitive deficits or mood disorders.


Assuntos
Hipocampo , Receptores de Estrogênio , Masculino , Feminino , Camundongos , Animais , Receptores de Estrogênio/genética , Potenciação de Longa Duração/genética , Sinapses/fisiologia , Cognição , Plasticidade Neuronal/genética
20.
J Neurosci ; 31(7): 2511-25, 2011 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-21325519

RESUMO

This report describes the behavioral and electrophysiological analysis of regulatable transgenic mice expressing mutant repeat domains of human Tau (Tau(RD)). Mice were generated to express Tau(RD) in two forms, differing in their propensity for ß-structure and thus in their tendency for aggregation ("pro-aggregant" or "anti-aggregant") (Mocanu et al., 2008). Only pro-aggregant mice show pronounced changes typical for Tau pathology in Alzheimer's disease (aggregation, missorting, hyperphosphorylation, synaptic and neuronal loss), indicating that the ß-propensity and hence the ability to aggregate is a key factor in the disease. We now tested the mice with regard to neuromotor parameters, behavior, learning and memory, and synaptic plasticity and correlated this with histological and biochemical parameters in different stages of switching Tau(RD) on or off. The mice are normal in neuromotor tests. However, pro-aggregant Tau(RD) mice are strongly impaired in memory and show pronounced loss of long-term potentiation (LTP), suggesting that Tau aggregation specifically perturbs these brain functions. Remarkably, when the expression of human pro-aggregant Tau(RD) is switched on for ∼ 10 months and off for ∼ 4 months, memory and LTP recover, whereas aggregates decrease moderately and change their composition from mixed human plus mouse Tau to mouse Tau only. Neuronal loss persists, but synapses are partially rescued. This argues that continuous presence of amyloidogenic pro-aggregant Tau(RD) constitutes the main toxic insult for memory and LTP, rather than the aggregates as such.


Assuntos
Potenciação de Longa Duração/genética , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Mutação/genética , Tauopatias , Proteínas tau/genética , Animais , Modelos Animais de Doenças , Doxiciclina/farmacologia , Força da Mão/fisiologia , Hipocampo/patologia , Hipocampo/ultraestrutura , Humanos , Técnicas In Vitro , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Testes Neuropsicológicos , Estrutura Terciária de Proteína , Percepção Espacial/fisiologia , Sinapses/patologia , Sinapses/ultraestrutura , Tauopatias/metabolismo , Tauopatias/patologia , Tauopatias/fisiopatologia , Fatores de Tempo , Proteínas tau/metabolismo
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