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1.
Int J Mol Sci ; 22(2)2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33445678

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a rapid accumulation of amyloid ß (Aß) protein in the hippocampus, which impairs synaptic structures and neuronal signal transmission, induces neuronal loss, and diminishes memory and cognitive functions. The present study investigated the impact of neuregulin 1 (NRG1)-ErbB4 signaling on the impairment of neural networks underlying hippocampal long-term potentiation (LTP) in 5xFAD mice, a model of AD with greater symptom severity than that of TG2576 mice. Specifically, we observed parvalbumin (PV)-containing hippocampal interneurons, the effect of NRG1 on hippocampal LTP, and the functioning of learning and memory. We found a significant decrease in the number of PV interneurons in 11-month-old 5xFAD mice. Moreover, synaptic transmission in the 5xFAD mice decreased at 6 months of age. The 11-month-old transgenic AD mice showed fewer inhibitory PV neurons and impaired NRG1-ErbB4 signaling than did wild-type mice, indicating that the former exhibit the impairment of neuronal networks underlying LTP in the hippocampal Schaffer-collateral pathway. In conclusion, this study confirmed the impaired LTP in 5xFAD mice and its association with aberrant NRG1-ErbB signaling in the neuronal network.


Assuntos
Envelhecimento/patologia , Doença de Alzheimer/patologia , Região CA1 Hipocampal/patologia , Potenciação de Longa Duração/fisiologia , Rede Nervosa/patologia , Neurônios/patologia , Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Região CA1 Hipocampal/metabolismo , Cognição/fisiologia , Modelos Animais de Doenças , Feminino , Interneurônios/metabolismo , Interneurônios/patologia , Aprendizagem/fisiologia , Masculino , Memória/fisiologia , Camundongos , Camundongos Transgênicos , Rede Nervosa/metabolismo , Neuregulina-1/metabolismo , Neurônios/metabolismo , Parvalbuminas/metabolismo , Receptor ErbB-4/metabolismo , Transdução de Sinais/fisiologia , Transmissão Sináptica/fisiologia
2.
J Stroke Cerebrovasc Dis ; 30(3): 105550, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33341564

RESUMO

BACKGROUND: Accumulating evidences have demonstrated the roles of several long non-coding RNAs (lncRNAs) in depression. We aim to examine the capabilities of lncRNA growth arrest-specific transcript 5 (GAS5) on mice with depression-like behaviors and the mechanism of action. METHODS: Fifty-six healthy mice were selected for model establishment. Morris water maze test and trapeze test were performed for evaluating learning and memory ability. The binding relationship between lncRNA GAS5 and microRNA-26a (miR-26a) and the target relationship between miR-26a and EGR1 were verified by dual-luciferase reporter gene assay. The apoptosis of neurons in the hippocampal CA1 region of mice was detected by TUNEL staining. The expression of inflammatory factors, lncRNA GAS5, miR-26a, early growth response gene 1 (EGR1), phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway- and apoptosis-related factors in hippocampal tissues was tested by RT-qPCR and western blot analysis. RESULTS: miR-26a expression was down-regulated while EGR1 and lncRNA GAS5 expression were up-regulated in hippocampal tissues of mice with depression-like behaviors. LncRNA GAS5 specifically bound to miR-26a and miR-26a targeted EGR1. Silencing of lncRNA GAS5 curtailed the release of inflammatory factors and the apoptosis of hippocampal neuron of mice with depression-like behaviors. EGR1 suppressed PI3K/AKT pathway activation to promote the release of inflammatory factors and the apoptosis of hippocampal neurons in mice with depression-like behaviors. CONCLUSION: Our study provides evidence that silencing of lncRNA GAS5 could activate PI3K/AKT pathway to protect hippocampal neurons against damage in mice with depression-like behaviors by regulating the miR-26a/EGR1 axis.


Assuntos
Apoptose , Comportamento Animal , Região CA1 Hipocampal/metabolismo , Depressão/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , MicroRNAs/metabolismo , Neurônios/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Região CA1 Hipocampal/patologia , Região CA1 Hipocampal/fisiopatologia , Depressão/genética , Depressão/patologia , Depressão/psicologia , Modelos Animais de Doenças , Regulação para Baixo , Proteína 1 de Resposta de Crescimento Precoce/genética , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Neurônios/patologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/genética , Transdução de Sinais
3.
Int J Mol Sci ; 21(24)2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33322419

RESUMO

This review is focused on the description and discussion of the alterations of astrocytes and microglia interplay in models of Alzheimer's disease (AD). AD is an age-related neurodegenerative pathology with a slowly progressive and irreversible decline of cognitive functions. One of AD's histopathological hallmarks is the deposition of amyloid beta (Aß) plaques in the brain. Long regarded as a non-specific, mere consequence of AD pathology, activation of microglia and astrocytes is now considered a key factor in both initiation and progression of the disease, and suppression of astrogliosis exacerbates neuropathology. Reactive astrocytes and microglia overexpress many cytokines, chemokines, and signaling molecules that activate or damage neighboring cells and their mutual interplay can result in virtuous/vicious cycles which differ in different brain regions. Heterogeneity of glia, either between or within a particular brain region, is likely to be relevant in healthy conditions and disease processes. Differential crosstalk between astrocytes and microglia in CA1 and CA3 areas of the hippocampus can be responsible for the differential sensitivity of the two areas to insults. Understanding the spatial differences and roles of glia will allow us to assess how these interactions can influence the state and progression of the disease, and will be critical for identifying therapeutic strategies.


Assuntos
Hipocampo/metabolismo , Neuroglia/citologia , Neurônios/citologia , Neurônios/fisiologia , Animais , Animais Geneticamente Modificados , Astrócitos/metabolismo , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/metabolismo , Região CA3 Hipocampal/citologia , Região CA3 Hipocampal/metabolismo , Humanos , Microscopia Confocal , Neuroglia/fisiologia , Placa Amiloide/metabolismo
4.
Int J Mol Sci ; 21(24)2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33322577

RESUMO

d-serine is the major co-agonist of N-methyl-D-aspartate receptors (NMDAR) at CA3/CA1 hippocampal synapses, the activation of which drives long-term potentiation (LTP). The use of mice with targeted deletion of the serine racemase (SR) enzyme has been an important tool to uncover the physiological and pathological roles of D-serine. To date, some uncertainties remain regarding the direction of LTP changes in SR-knockout (SR-KO) mice, possibly reflecting differences in inhibitory GABAergic tone in the experimental paradigms used in the different studies. On the one hand, our extracellular recordings in hippocampal slices show that neither isolated NMDAR synaptic potentials nor LTP were altered in SR-KO mice. This was associated with a compensatory increase in hippocampal levels of glycine, another physiologic NMDAR co-agonist. SR-KO mice displayed no deficits in spatial learning, reference memory and cognitive flexibility. On the other hand, SR-KO mice showed a weaker LTP and a lower increase in NMDAR potentials compared to controls when GABAA receptors were pharmacologically blocked. Our results indicate that depletion of endogenous D-serine caused a reduced inhibitory activity in CA1 hippocampal networks, altering the excitatory/inhibitory balance, which contributes to preserve functional plasticity at synapses and to maintain related cognitive abilities.


Assuntos
Região CA1 Hipocampal/metabolismo , Racemases e Epimerases/metabolismo , Aminoácidos/metabolismo , Animais , Eletrofisiologia , Hipocampo/metabolismo , Potenciação de Longa Duração/fisiologia , Masculino , Memória/fisiologia , Camundongos , Plasticidade Neuronal/fisiologia , Racemases e Epimerases/genética , Receptores de N-Metil-D-Aspartato/metabolismo
5.
Anesth Analg ; 131(5): 1616-1625, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33079886

RESUMO

BACKGROUND: Anesthesia in pregnant rodents causes neurotoxicity in fetal and offspring rodents. However, the underlying mechanisms and targeted treatments remain largely to be determined. Isoflurane and propofol are among commonly used anesthetics. Thus, we set out to investigate whether propofol can mitigate the isoflurane-induced neurotoxicity in mice. METHODS: Pregnant C57BL/6 mice at gestational day 15 (G15) were randomly assigned to 4 groups: control, isoflurane, propofol, and isoflurane plus propofol. Levels of interleukin (IL)-6 and poly-ADP ribose polymerase (PARP) fragment were measured in the brains of G15 embryos, and levels of postsynaptic density (PSD)-95 and synaptophysin were determined in the hippocampal tissues of postnatal day 31 (P31) offspring using Western blotting and immunohistochemical staining. Learning and memory functions in P31 offspring were determined using a Morris water maze test. RESULTS: Isoflurane anesthesia in pregnant mice at G15 significantly increased brain IL-6 (222.6% ± 36.45% vs 100.5% ± 3.43%, P < .0001) and PARP fragment (384.2% ± 50.87% vs 99.59% ± 3.25%, P < .0001) levels in fetal mice and reduced brain PSD-95 (30.76% ± 2.03% vs 100.8% ± 2.25%, P < .0001) and synaptophysin levels in cornu ammonis (CA) 1 region (57.08% ± 4.90% vs 100.6% ± 2.20%, P < .0001) and dentate gyrus (DG; 56.47% ± 3.76% vs 99.76% ± 1.09%, P < .0001) in P31 offspring. Isoflurane anesthesia also impaired cognitive function in offspring at P31. Propofol significantly mitigated isoflurane-induced increases in brain IL-6 (117.5% ± 10.37% vs 222.6% ± 36.45%, P < .0001) and PARP fragment (205.1% ± 35.99% vs 384.2% ± 50.87%, P < .0001) levels in fetal mice, as well as reductions in PSD-95 (49.79% ± 3.43% vs 30.76% ± 2.03%, P < .0001) and synaptophysin levels in CA1 region (85.57% ± 2.97% vs 57.08% ± 4.90%, P < .0001) and DG (85.05% ± 1.87% vs 56.47% ± 3.76%, P < .0001) in hippocampus of P31 offspring. Finally, propofol attenuated isoflurane-induced cognitive impairment in offspring. CONCLUSIONS: These findings suggest that gestational isoflurane exposure in mice induces neuroinflammation and apoptosis in embryos and causes cognitive impairment in offspring. Propofol can attenuate these isoflurane-induced detrimental effects.


Assuntos
Anestésicos Inalatórios/toxicidade , Anestésicos Intravenosos/farmacologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/prevenção & controle , Isoflurano/antagonistas & inibidores , Isoflurano/toxicidade , Doenças do Sistema Nervoso/induzido quimicamente , Doenças do Sistema Nervoso/prevenção & controle , Propofol/farmacologia , Animais , Animais Recém-Nascidos , Química Encefálica/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Disfunção Cognitiva/psicologia , Proteína 4 Homóloga a Disks-Large/metabolismo , Feminino , Feto , Interleucina-6/metabolismo , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Poli(ADP-Ribose) Polimerase-1/metabolismo , Gravidez , Sinaptofisina/metabolismo
6.
Proc Natl Acad Sci U S A ; 117(38): 23527-23538, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32907943

RESUMO

Clathrin light chain (CLC) subunits in vertebrates are encoded by paralogous genes CLTA and CLTB, and both gene products are alternatively spliced in neurons. To understand how this CLC diversity influences neuronal clathrin function, we characterized the biophysical properties of clathrin comprising individual CLC variants for correlation with neuronal phenotypes of mice lacking either CLC-encoding gene. CLC splice variants differentially influenced clathrin knee conformation within assemblies, and clathrin with neuronal CLC mixtures was more effective in membrane deformation than clathrin with single neuronal isoforms nCLCa or nCLCb. Correspondingly, electrophysiological recordings revealed that neurons from mice lacking nCLCa or nCLCb were both defective in synaptic vesicle replenishment. Mice with only nCLCb had a reduced synaptic vesicle pool and impaired neurotransmission compared to WT mice, while nCLCa-only mice had increased synaptic vesicle numbers, restoring normal neurotransmission. These findings highlight differences between the CLC isoforms and show that isoform mixing influences tissue-specific clathrin activity in neurons, which requires their functional balance.


Assuntos
Cadeias Leves de Clatrina , Vesículas Sinápticas/química , Vesículas Sinápticas/metabolismo , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/metabolismo , Células Cultivadas , Cadeias Leves de Clatrina/química , Cadeias Leves de Clatrina/genética , Cadeias Leves de Clatrina/metabolismo , Camundongos , Camundongos Knockout , Neurônios/citologia , Neurônios/metabolismo , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo
7.
Nat Commun ; 11(1): 3451, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32651370

RESUMO

When our experience violates our predictions, it is adaptive to upregulate encoding of novel information, while down-weighting retrieval of erroneous memory predictions to promote an updated representation of the world. We asked whether mnemonic prediction errors promote hippocampal encoding versus retrieval states, as marked by distinct network connectivity between hippocampal subfields. During fMRI scanning, participants were cued to internally retrieve well-learned complex room-images and were then presented with either an identical or a modified image (0-4 changes). In the left hemisphere, we find that CA1-entorhinal connectivity increases, and CA1-CA3 connectivity decreases, with the number of changes. Further, in the left CA1, the similarity between activity patterns during cued-retrieval of the learned room and during the image is lower when the image includes changes, consistent with a prediction error signal in CA1. Our findings provide a mechanism by which mnemonic prediction errors may drive memory updating-by biasing hippocampal states.


Assuntos
Cognição/fisiologia , Hipocampo/metabolismo , Hipocampo/fisiologia , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/fisiologia , Córtex Entorrinal/metabolismo , Córtex Entorrinal/fisiologia , Humanos , Aprendizagem/fisiologia , Imagem por Ressonância Magnética , Memória de Longo Prazo/fisiologia
8.
Toxicol Lett ; 332: 192-201, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32693020

RESUMO

Fenvalerate, a synthetic pyrethroid insecticide, is an environmental endocrine disruptor and neurodevelopmental toxicant. An early report found that pubertal exposure to high-dose fenvalerate impaired cognitive and behavioral development. Here, we aimed to further investigate the effect of pubertal exposure to low-dose fenvalerate on cognitive and behavioral development. Mice were orally administered with fenvalerate (0.2, 1.0 and 5.0 mg/kg) daily from postnatal day (PND) 28 to PND56. Learning and memory were assessed by Morris water maze. Anxiety-related activities were detected by open-field and elevated plus-maze. Increased anxiety activities were observed only in females exposed to fenvalerate. Spatial learning and memory were damaged only in females exposed to fenvalerate. Histopathology observed numerous scattered shrinking neurons and nuclear pyknosis in hippocampal CA1 region. Neuronal density was reduced in hippocampal CA1 region of fenvalerate-exposed mice. Mechanistically, hippocampal thyroid hormone receptor (TR)ß1 was down-regulated in a dose-dependent manner in females. In addition, TRα1 was declined only in females exposed to 5.0 mg/kg fenvalerate. Taken together, these suggests that pubertal exposure to low-dose fenvalerate impairs cognitive and behavioral development in a gender-dependent manner. Hippocampal TR signaling may be, at least partially, involved in fenvalerate-induced impairment of cognitive and behavioral development.


Assuntos
Transtornos Cognitivos/induzido quimicamente , Hipocampo/metabolismo , Inseticidas/toxicidade , Nitrilos/toxicidade , Piretrinas/toxicidade , Transdução de Sinais/efeitos dos fármacos , Hormônios Tireóideos , Animais , Ansiedade/induzido quimicamente , Ansiedade/psicologia , Peso Corporal/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Transtornos Cognitivos/psicologia , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Disruptores Endócrinos , Feminino , Hipocampo/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Neurônios/patologia , Receptores dos Hormônios Tireóideos/efeitos dos fármacos , Caracteres Sexuais
9.
Nat Commun ; 11(1): 3492, 2020 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-32661319

RESUMO

Ventral hippocampal CA1 (vCA1) projections to the amygdala are necessary for contextual fear memory. Here we used in vivo Ca2+ imaging in mice to assess the temporal dynamics by which ensembles of vCA1 neurons mediate encoding and retrieval of contextual fear memories. We found that a subset of vCA1 neurons were responsive to the aversive shock during context conditioning, their activity was necessary for memory encoding, and these shock-responsive neurons were enriched in the vCA1 projection to the amygdala. During memory retrieval, a population of vCA1 neurons became correlated with shock-encoding neurons, and the magnitude of synchronized activity within this population was proportional to memory strength. The emergence of these correlated networks was disrupted by inhibiting vCA1 shock responses during memory encoding. Thus, our findings suggest that networks of cells that become correlated with shock-responsive neurons in vCA1 are essential components of contextual fear memory ensembles.


Assuntos
Região CA1 Hipocampal/metabolismo , Medo/fisiologia , Memória/fisiologia , Algoritmos , Tonsila do Cerebelo/metabolismo , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL
10.
Life Sci ; 256: 118018, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32598935

RESUMO

Aim While stress causes brain dysfunction, crocin (as an active component of saffron) and exercise (as part of a healthy lifestyle) improve stress-induced memory impairment. The present study investigated the protective effects of crocin administration, exercise, and crocin-accompanied exercise on neuronal excitability and long-term potentiation (LTP) at the CA1 of hippocampus as well as serum corticosterone and glucose levels in rats subjected to chronic unpredictable stress (CUS). MAIN METHODS: Forty-eight male Wistar rats were randomly allocated to six groups: Control, Sham, CUS, CUS-Crocin30, CUS-Exercise, and CUS-Crocin30-Exercise. The chronic unpredictable stress and treadmill running at 20-21 m/min were applied 2 h/day and 1 h/day, respectively, for 21 days. Crocin (30 mg/kg) was daily intraperitoneally injected to the rats. Electrophysiological variables were recorded from the CA1 of hippocampus. While corticosterone and glucose levels were also measured. KEY FINDINGS: CUS and CUS-Exercise significantly attenuated excitability and LTP. Compared to the CUS and CUS-Exercise treatments, CUS-Crocin30 and CUS-Crocin30-Exercise led to significant increases in slope and amplitude of field excitatory postsynaptic potential. The changes in serum corticosterone and glucose levels nearly matched the electrophysiological data. SIGNIFICANCE: CUS was found to be a highly destructive stress as it failed to allow exercises to edify the CUS-induced memory deficit. This is while crocin (as a herbal drug) was found more effective than exercise (as a daily routine) in remedying the CUS-induced memory deficit. Also, although the treatment with crocin-accompanied exercise did help recovery from the CUS-induced memory deficit, the interaction of crocin administration and exercise had no synergic effects; the protective effect observed was due to crocin administration rather than the exercise.


Assuntos
Carotenoides/farmacologia , Transtornos da Memória/terapia , Condicionamento Físico Animal/fisiologia , Estresse Psicológico/terapia , Animais , Glicemia/metabolismo , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Corticosterona/sangue , Modelos Animais de Doenças , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Masculino , Transtornos da Memória/etiologia , Distribuição Aleatória , Ratos , Ratos Wistar , Estresse Psicológico/complicações
11.
Sci Rep ; 10(1): 7494, 2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32366857

RESUMO

O-GlcNAcylation, a post-translational modification involving O-linkage of ß-N-acetylglucosamine to Ser/Thr residues on target proteins, is increasingly recognized as a critical regulator of synaptic function. Enzymes that catalyze O-GlcNAcylation are found at both presynaptic and postsynaptic sites, and O-GlcNAcylated proteins localize to synaptosomes. An acute increase in O-GlcNAcylation can affect neuronal communication by inducing long-term depression (LTD) of excitatory transmission at hippocampal CA3-CA1 synapses, as well as suppressing hyperexcitable circuits in vitro and in vivo. Despite these findings, to date, no studies have directly examined how O-GlcNAcylation modulates the efficacy of inhibitory neurotransmission. Here we show an acute increase in O-GlcNAc dampens GABAergic currents onto principal cells in rodent hippocampus likely through a postsynaptic mechanism, and has a variable effect on the excitation/inhibition balance. The overall effect of increased O-GlcNAc is reduced synaptically-driven spike probability via synaptic depression and decreased intrinsic excitability. Our results position O-GlcNAcylation as a novel regulator of the overall excitation/inhibition balance and neuronal output.


Assuntos
Região CA1 Hipocampal/metabolismo , Região CA3 Hipocampal/metabolismo , Plasticidade Neuronal , Processamento de Proteína Pós-Traducional , Receptores de GABA-A/metabolismo , Sinapses/metabolismo , Transmissão Sináptica , Animais , Feminino , Glicosilação , Masculino , Ratos , Ratos Sprague-Dawley
12.
Neuron ; 106(6): 992-1008.e9, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32320644

RESUMO

Astrocytes play essential roles in brain function by supporting synaptic connectivity and associated circuits. How these roles are regulated by transcription factors is unknown. Moreover, there is emerging evidence that astrocytes exhibit regional heterogeneity, and the mechanisms controlling this diversity remain nascent. Here, we show that conditional deletion of the transcription factor nuclear factor I-A (NFIA) in astrocytes in the adult brain results in region-specific alterations in morphology and physiology that are mediated by selective DNA binding. Disruptions in astrocyte function following loss of NFIA are most pronounced in the hippocampus, manifested by impaired interactions with neurons, coupled with diminution of learning and memory behaviors. These changes in hippocampal astrocytes did not affect basal neuronal properties but specifically inhibited synaptic plasticity, which is regulated by NFIA in astrocytes through calcium-dependent mechanisms. Together, our studies reveal region-specific transcriptional dependencies for astrocytes and identify astrocytic NFIA as a key transcriptional regulator of hippocampal circuits.


Assuntos
Astrócitos/metabolismo , Encéfalo/metabolismo , Cálcio/metabolismo , Regulação da Expressão Gênica , Aprendizagem/fisiologia , Fatores de Transcrição NFI/genética , Animais , Astrócitos/fisiologia , Encéfalo/citologia , Encéfalo/fisiopatologia , Tronco Encefálico/citologia , Tronco Encefálico/metabolismo , Tronco Encefálico/fisiopatologia , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/fisiopatologia , Hipocampo/citologia , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Potenciação de Longa Duração/fisiologia , Memória/fisiologia , Camundongos , Camundongos Knockout , Vias Neurais , Plasticidade Neuronal , Neurônios , Bulbo Olfatório/citologia , Bulbo Olfatório/metabolismo , Bulbo Olfatório/fisiopatologia , Técnicas de Patch-Clamp , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Memória Espacial/fisiologia
13.
J Neurosci ; 40(22): 4266-4276, 2020 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-32327534

RESUMO

Synaptic plasticity is triggered by different patterns of network activity. Here, we investigated how LTP in CA3-CA1 synapses induced by different stimulation patterns is affected by tonic GABAA conductances in rat hippocampal slices. Spike-timing-dependent LTP was induced by pairing Schaffer collateral stimulation with antidromic stimulation of CA1 pyramidal neurons. Theta-burst-induced LTP was induced by theta-burst stimulation of Schaffer collaterals. We mimicked increased tonic GABAA conductance by bath application of 30 µm GABA. Surprisingly, tonic GABAA conductance selectively suppressed theta-burst-induced LTP but not spike-timing-dependent LTP. We combined whole-cell patch-clamp electrophysiology, two-photon Ca2+ imaging, glutamate uncaging, and mathematical modeling to dissect the mechanisms underlying these differential effects of tonic GABAA conductance. We found that Ca2+ transients during pairing of an action potential with an EPSP were less sensitive to tonic GABAA conductance-induced shunting inhibition than Ca2+ transients induced by EPSP burst. Our results may explain how different forms of memory are affected by increasing tonic GABAA conductances under physiological or pathologic conditions, as well as under the influence of substances that target extrasynaptic GABAA receptors (e.g., neurosteroids, sedatives, antiepileptic drugs, and alcohol).SIGNIFICANCE STATEMENT Brain activity is associated with neuronal firing and synaptic signaling among neurons. Synaptic plasticity represents a mechanism for learning and memory. However, some neurotransmitters that escape the synaptic cleft or are released by astrocytes can target extrasynaptic receptors. Extrasynaptic GABAA receptors mediate tonic conductances that reduce the excitability of neurons by shunting. This results in the decreased ability for neurons to fire action potentials, but when action potentials are successfully triggered, tonic conductances are unable to reduce them significantly. As such, tonic GABAA conductances have minimal effects on spike-timing-dependent synaptic plasticity while strongly attenuating the plasticity evoked by EPSP bursts. Our findings shed light on how changes in tonic conductances can selectively affect different forms of learning and memory.


Assuntos
Região CA1 Hipocampal/metabolismo , Potenciais Pós-Sinápticos Excitadores , Potenciação de Longa Duração , Receptores de GABA-A/metabolismo , Ritmo Teta , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/fisiologia , Cálcio/metabolismo , Ácido Glutâmico/metabolismo , Masculino , Células Piramidais/metabolismo , Células Piramidais/fisiologia , Ratos , Ratos Sprague-Dawley
14.
Sci Rep ; 10(1): 6507, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32300196

RESUMO

Understanding the root causes of neuronal vulnerability to ischemia is paramount to the development of new therapies for stroke. Transient global cerebral ischemia (tGCI) leads to selective neuronal cell death in the CA1 sub-region of the hippocampus, while the neighboring CA3 sub-region is left largely intact. By studying factors pertaining to such selective vulnerability, we can develop therapies to enhance outcome after stroke. Using untargeted liquid chromatography-mass spectrometry, we analyzed temporal metabolomic changes in CA1 and CA3 hippocampal areas following tGCI in rats till the setting of neuronal apoptosis. 64 compounds in CA1 and 74 in CA3 were found to be enriched and statistically significant following tGCI. Pathway analysis showed that pyrimidine and purine metabolism pathways amongst several others to be enriched after tGCI in CA1 and CA3. Metabolomics analysis was able to capture very early changes following ischemia. We detected 6 metabolites to be upregulated and 6 to be downregulated 1 hour after tGCI in CA1 versus CA3. Several metabolites related to apoptosis and inflammation were differentially expressed in both regions after tGCI. We offer a new insight into the process of neuronal apoptosis, guided by metabolomic profiling that was not performed to such an extent previously.


Assuntos
Isquemia Encefálica/metabolismo , Ataque Isquêmico Transitório/genética , Neurônios/metabolismo , Purinas/metabolismo , Pirimidinas/metabolismo , Animais , Apoptose/genética , Isquemia Encefálica/patologia , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/patologia , Região CA3 Hipocampal/metabolismo , Cromatografia Líquida , Regulação da Expressão Gênica/genética , Humanos , Ataque Isquêmico Transitório/metabolismo , Ataque Isquêmico Transitório/patologia , Espectrometria de Massas , Metabolômica/métodos , Neurônios/patologia , Ratos , Transdução de Sinais/genética
15.
Environ Toxicol ; 35(9): 961-970, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32255272

RESUMO

Benzo[a]pyrene (B[a]P) is recognized as a neurotoxic pollutant to mammals, which could impair learning and memory function. Although there is some evidence to suggest that N-methyl-d-aspartate receptor (NMDAR), a glutamate receptor and ion channel protein in nerve cells, is involved into the B[a]P induced neurotoxicity, the exact molecular mechanisms remain to be elucidated, particularly the effects of B[a]P on the NMDAR downstream signaling transduction pathways. In the present study, we examined the neurotoxicity of sub-chronic administrated B[a]P on male Sprague-Dawley rats. Our data suggested that B[a]P exposure caused significant deficits in learning and memory function and the impairment of hippocampal LTP in rats. Further mechanistic studies indicate that B[a]P-induced learning and memory deficits are associated with the inhibition of NMDAR NR1 subunit transcription and protein phosphorylation. More importantly, the inactivation of CaMK II/PKC/PKA-ERK-CREB signaling pathways in hippocampus was detected at both the 2.5 and 6.25 mg/kg B[a]P-treated groups, indicating that multiple targets in NMDAR and downstream signaling pathways are involved in the B[a]P-induced neurotoxicity.


Assuntos
Benzo(a)pireno/toxicidade , Região CA1 Hipocampal/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Proteína Quinase C/metabolismo , Receptores de Glutamato/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Região CA1 Hipocampal/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fosforilação , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
16.
Brain ; 143(3): 976-992, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32091109

RESUMO

Research into hippocampal self-regulation abilities may help determine the clinical significance of hippocampal hyperactivity throughout the pathophysiological continuum of Alzheimer's disease. In this study, we aimed to identify the effects of amyloid-ß peptide 42 (amyloid-ß42) and phosphorylated tau on the patterns of functional connectomics involved in hippocampal downregulation. We identified 48 cognitively unimpaired participants (22 with elevated CSF amyloid-ß peptide 42 levels, 15 with elevated CSF phosphorylated tau levels, mean age of 62.705 ± 4.628 years), from the population-based 'Alzheimer's and Families' study, with baseline MRI, CSF biomarkers, APOE genotyping and neuropsychological evaluation. We developed a closed-loop, real-time functional MRI neurofeedback task with virtual reality and tailored it for training downregulation of hippocampal subfield cornu ammonis 1 (CA1). Neurofeedback performance score, cognitive reserve score, hippocampal volume, number of apolipoprotein ε4 alleles and sex were controlled for as confounds in all cross-sectional analyses. First, using voxel-wise multiple regression analysis and controlling for CSF biomarkers, we identified the effect of healthy ageing on eigenvector centrality, a measure of each voxel's overall influence based on iterative whole-brain connectomics, during hippocampal CA1 downregulation. Then, controlling for age, we identified the effects of abnormal CSF amyloid-ß42 and phosphorylated tau levels on eigenvector centrality during hippocampal CA1 downregulation. Across subjects, our main findings during hippocampal downregulation were: (i) in the absence of abnormal biomarkers, age correlated with eigenvector centrality negatively in the insula and midcingulate cortex, and positively in the inferior temporal gyrus; (ii) abnormal CSF amyloid-ß42 (<1098) correlated negatively with eigenvector centrality in the anterior cingulate cortex and primary motor cortex; and (iii) abnormal CSF phosphorylated tau levels (>19.2) correlated with eigenvector centrality positively in the ventral striatum, anterior cingulate and somatosensory cortex, and negatively in the precuneus and orbitofrontal cortex. During resting state functional MRI, similar eigenvector centrality patterns in the cingulate had previously been associated to CSF biomarkers in mild cognitive impairment and dementia patients. Using the developed closed-loop paradigm, we observed such patterns, which are characteristic of advanced disease stages, during a much earlier presymptomatic phase. In the absence of CSF biomarkers, our non-invasive, interactive, adaptive and gamified neuroimaging procedure may provide important information for clinical prognosis and monitoring of therapeutic efficacy. We have released the developed paradigm and analysis pipeline as open-source software to facilitate replication studies.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Região CA1 Hipocampal/metabolismo , Neurorretroalimentação/métodos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Fatores Etários , Idoso , Doença de Alzheimer/complicações , Apolipoproteína E4/genética , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Disfunção Cognitiva/complicações , Disfunção Cognitiva/metabolismo , Conectoma , Estudos Transversais , Regulação para Baixo , Feminino , Genótipo , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Testes Neuropsicológicos , Fosforilação , Software , Realidade Virtual
17.
Molecules ; 25(3)2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32041202

RESUMO

Alzheimer's disease (AD) is a complex and chronic neurodegenerative disorder that involves a progressive and severe decline in cognition and memory. During the last few decades a considerable amount of research has been done in order to better understand tau-pathology, inflammatory activity and neuronal synapse loss in AD, all of them contributing to cognitive decline. Early hippocampal network dysfunction is one of the main factors associated with cognitive decline in AD. Much has been published about amyloid-beta1-42 (Aß1-42)-mediated excitotoxicity in AD. However, increasing evidence demonstrates that the remodeling of the inhibitory gamma-aminobutyric acid (GABAergic) system contributes to the excitatory/inhibitory (E/I) disruption in the AD hippocampus, but the underlying mechanisms are not well understood. In the present study, we show that hippocampal injection of Aß1-42 is sufficient to induce cognitive deficits 7 days post-injection. We demonstrate using in vitro whole-cell patch-clamping an increased inhibitory GABAergic tonic conductance mediated by extrasynaptic type A GABA receptors (GABAARs), recorded in the CA1 region of the mouse hippocampus following Aß1-42 micro injection. Such alterations in GABA neurotransmission and/or inhibitory GABAARs could have a significant impact on both hippocampal structure and function, causing E/I balance disruption and potentially contributing to cognitive deficits in AD.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Região CA1 Hipocampal/metabolismo , Hipocampo/metabolismo , Células Piramidais/metabolismo , Ácido gama-Aminobutírico/metabolismo , Doença de Alzheimer/metabolismo , Animais , Masculino , Memória/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de GABA-A/metabolismo , Sinapses/metabolismo , Transmissão Sináptica/fisiologia
18.
J Neuroinflammation ; 17(1): 45, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32007102

RESUMO

BACKGROUND: G-protein-coupled estrogen receptor (GPER/GPR30) is a novel membrane-associated estrogen receptor that can induce rapid kinase signaling in various cells. Activation of GPER can prevent hippocampal neuronal cell death following transient global cerebral ischemia (GCI), although the mechanisms remain unclear. In the current study, we sought to address whether GPER activation exerts potent anti-inflammatory effects in the rat hippocampus after GCI as a potential mechanism to limit neuronal cell death. METHODS: GCI was induced by four-vessel occlusion in ovariectomized female SD rats. Specific agonist G1 or antagonist G36 of GPER was administrated using minipump, and antisense oligonucleotide (AS) of interleukin-1ß receptor antagonist (IL1RA) was administrated using brain infusion kit. Protein expression of IL1RA, NF-κB-P65, phosphorylation of CREB (p-CREB), Bcl2, cleaved caspase 3, and microglial markers Iba1, CD11b, as well as inflammasome components NLRP3, ASC, cleaved caspase 1, and Cle-IL1ß in the hippocampal CA1 region were investigated by immunofluorescent staining and Western blot analysis. The Duolink II in situ proximity ligation assay (PLA) was performed to detect the interaction between NLRP3 and ASC. Immunofluorescent staining for NeuN and TUNEL analysis were used to analyze neuronal survival and apoptosis, respectively. We performed Barnes maze and Novel object tests to compare the cognitive function of the rats. RESULTS: The results showed that G1 attenuated GCI-induced elevation of Iba1 and CD11b in the hippocampal CA1 region at 14 days of reperfusion, and this effect was blocked by G36. G1 treatment also markedly decreased expression of the NLRP3-ASC-caspase 1 inflammasome and IL1ß activation, as well as downstream NF-κB signaling, the effects reversed by G36 administration. Intriguingly, G1 caused a robust elevation in neurons of a well-known endogenous anti-inflammatory factor IL1RA, which was reversed by G36 treatment. G1 also enhanced p-CREB level in the hippocampus, a transcription factor known to enhance expression of IL1RA. Finally, in vivo IL1RA-AS abolished the anti-inflammatory, neuroprotective, and anti-apoptotic effects of G1 after GCI and reversed the cognitive-enhancing effects of G1 at 14 days after GCI. CONCLUSIONS: Taken together, the current results suggest that GPER preserves cognitive function following GCI in part by exerting anti-inflammatory effects and enhancing the defense mechanism of neurons by upregulating IL1RA.


Assuntos
Isquemia Encefálica/metabolismo , Hipocampo/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Neurônios/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Apoptose , Isquemia Encefálica/psicologia , Região CA1 Hipocampal/metabolismo , Morte Celular , Sobrevivência Celular , Cognição , Feminino , Proteína Antagonista do Receptor de Interleucina 1/genética , Aprendizagem em Labirinto , Neurônios/patologia , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas-G/genética , Reconhecimento Psicológico , Fator de Transcrição RelA/metabolismo
19.
Int J Mol Sci ; 21(4)2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32093363

RESUMO

SNAP-25 is essential to activity-dependent vesicle fusion and neurotransmitter release in the nervous system. During early development and adulthood, SNAP-25 appears to have differential influences on short- and long-term synaptic plasticity. The involvement of SNAP-25 in these processes may be different at hippocampal and neocortical synapses because of the presence of two different splice variants, which are developmentally regulated. We show here that the isoform SNAP-25a, which is expressed first developmentally in rodent brain, contributes to developmental regulation of the expression of both long-term depression (LTD) and long-term potentiation (LTP) at Schaffer collateral-CA1 synapses in the hippocampus. In one month old mice lacking the developmentally later expressed isoform SNAP-25b, Schaffer collateral-CA1 synapses showed faster release kinetics, decreased LTP and enhanced LTD. By four months of age, SNAP-25b-deficient mice appeared to have compensated for the lack of the adult SNAP-25b isoform, now exhibiting larger LTP and no differences in LTD compared to wild type mice. Interestingly, learning a hippocampus-dependent task reversed the reductions in LTP, but not LTD, seen at one month of age. In four month old adult mice, learning prevented the compensatory up-regulation of LTD that we observed prior to training. These findings support the hypothesis that SNAP-25b promotes stronger LTP and weakens LTD at Schaffer collateral-CA1 synapses in young mice, and suggest that compensatory mechanisms can reverse alterations in synaptic plasticity associated with a lack of SNAP-25b, once mice reach adulthood.


Assuntos
Região CA1 Hipocampal/metabolismo , Aprendizagem , Potenciação de Longa Duração , Sinapses/metabolismo , Proteína 25 Associada a Sinaptossoma/metabolismo , Animais , Região CA1 Hipocampal/citologia , Feminino , Masculino , Camundongos , Camundongos Knockout , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Sinapses/genética , Proteína 25 Associada a Sinaptossoma/genética
20.
Sci Rep ; 10(1): 709, 2020 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959797

RESUMO

Recent evidence suggests that SNARE fusion machinery play critical roles in postsynaptic neurotransmitter receptor trafficking, which is essential for synaptic plasticity. However, the key SNAREs involved remain highly controversial; syntaxin-3 and syntaxin-4 are leading candidates for the syntaxin isoform underlying postsynaptic plasticity. In a previous study, we showed that pyramidal-neuron specific conditional knockout (cKO) of syntaxin-4 significantly reduces basal transmission, synaptic plasticity and impairs postsynaptic receptor trafficking. However, this does not exclude a role for syntaxin-3 in such processes. Here, we generated and analyzed syntaxin-3 cKO mice. Extracellular field recordings in hippocampal slices showed that syntaxin-3 cKO did not exhibit significant changes in CA1 basal neurotransmission or in paired-pulse ratios. Importantly, there were no observed differences during LTP in comparison to control mice. Syntaxin-3 cKO mice performed similarly as the controls in spatial and contextual learning tasks. Consistent with the minimal effects of syntaxin-3 cKO, syntaxin-3 mRNA level was very low in hippocampal and cortex pyramidal neurons, but strongly expressed in the corpus callosum and caudate axon fibers. Together, our data suggest that syntaxin-3 is dispensable for hippocampal basal neurotransmission and synaptic plasticity, and further supports the notion that syntaxin-4 is the major isoform mediating these processes.


Assuntos
Região CA1 Hipocampal/fisiologia , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Proteínas Qa-SNARE/fisiologia , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologia , Animais , Região CA1 Hipocampal/metabolismo , Corpo Caloso/metabolismo , Expressão Gênica , Técnicas In Vitro , Potenciação de Longa Duração/fisiologia , Camundongos Knockout , Proteínas Qa-SNARE/genética , Proteínas Qa-SNARE/metabolismo , RNA Mensageiro/metabolismo
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