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1.
Transl Psychiatry ; 11(1): 366, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34226487

RESUMO

Increasing evidence indicates lithium (Li+) efficacy in neuropsychiatry, pointing to overlapping mechanisms that occur within distinct neuronal populations. In fact, the same pathway depending on which circuitry operates may fall in the psychiatric and/or neurological domains. Li+ restores both neurotransmission and brain structure unveiling that psychiatric and neurological disorders share common dysfunctional molecular and morphological mechanisms, which may involve distinct brain circuitries. Here an overview is provided concerning the therapeutic/neuroprotective effects of Li+ in different neuropsychiatric disorders to highlight common molecular mechanisms through which Li+ produces its mood-stabilizing effects and to what extent these overlap with plasticity in distinct brain circuitries. Li+ mood-stabilizing effects are evident in typical bipolar disorder (BD) characterized by a cyclic course of mania or hypomania followed by depressive episodes, while its efficacy is weaker in the opposite pattern. We focus here on neural adaptations that may underlie psychostimulant-induced psychotic development and to dissect, through the sensitization process, which features are shared in BD and other psychiatric disorders, including schizophrenia. The multiple functions of Li+ highlighted here prove its exceptional pharmacology, which may help to elucidate its mechanisms of action. These may serve as a guide toward a multi-drug strategy. We propose that the onset of sensitization in a specific BD subtype may predict the therapeutic efficacy of Li+. This model may help to infer in BD which molecular mechanisms are relevant to the therapeutic efficacy of Li+.


Assuntos
Transtorno Bipolar , Lítio , Antimaníacos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Humanos , Lítio/uso terapêutico , Compostos de Lítio/farmacologia , Plasticidade Neuronal , Neuroproteção
2.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200797

RESUMO

Although sex differences in the brain are prevalent, the knowledge about mechanisms underlying sex-related effects on normal and pathological brain functioning is rather poor. It is known that female and male brains differ in size and connectivity. Moreover, those differences are related to neuronal morphology, synaptic plasticity, and molecular signaling pathways. Among different processes assuring proper synapse functions are posttranslational modifications, and among them, S-palmitoylation (S-PALM) emerges as a crucial mechanism regulating synaptic integrity. Protein S-PALM is governed by a family of palmitoyl acyltransferases, also known as DHHC proteins. Here we focused on the sex-related functional importance of DHHC7 acyltransferase because of its S-PALM action over different synaptic proteins as well as sex steroid receptors. Using the mass spectrometry-based PANIMoni method, we identified sex-dependent differences in the S-PALM of synaptic proteins potentially involved in the regulation of membrane excitability and synaptic transmission as well as in the signaling of proteins involved in the structural plasticity of dendritic spines. To determine a mechanistic source for obtained sex-dependent changes in protein S-PALM, we analyzed synaptoneurosomes isolated from DHHC7-/- (DHHC7KO) female and male mice. Our data showed sex-dependent action of DHHC7 acyltransferase. Furthermore, we revealed that different S-PALM proteins control the same biological processes in male and female synapses.


Assuntos
Aciltransferases/fisiologia , Lipoilação , Plasticidade Neuronal , Neurônios/fisiologia , Processamento de Proteína Pós-Traducional , Sinapses/fisiologia , Transmissão Sináptica , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/citologia , Fatores Sexuais
3.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34201943

RESUMO

The regulator of G-protein signaling 14 (RGS14) is a multifunctional signaling protein that regulates post synaptic plasticity in neurons. RGS14 is expressed in the brain regions essential for learning, memory, emotion, and stimulus-induced behaviors, including the basal ganglia, limbic system, and cortex. Behaviorally, RGS14 regulates spatial and object memory, female-specific responses to cued fear conditioning, and environmental- and psychostimulant-induced locomotion. At the cellular level, RGS14 acts as a scaffolding protein that integrates G protein, Ras/ERK, and calcium/calmodulin signaling pathways essential for spine plasticity and cell signaling, allowing RGS14 to naturally suppress long-term potentiation (LTP) and structural plasticity in hippocampal area CA2 pyramidal cells. Recent proteomics findings indicate that RGS14 also engages the actomyosin system in the brain, perhaps to impact spine morphogenesis. Of note, RGS14 is also a nucleocytoplasmic shuttling protein, where its role in the nucleus remains uncertain. Balanced nuclear import/export and dendritic spine localization are likely essential for RGS14 neuronal functions as a regulator of synaptic plasticity. Supporting this idea, human genetic variants disrupting RGS14 localization also disrupt RGS14's effects on plasticity. This review will focus on the known and unexplored roles of RGS14 in cell signaling, physiology, disease and behavior.


Assuntos
Encéfalo/metabolismo , Plasticidade Neuronal , Proteínas RGS/genética , Potenciais Sinápticos , Animais , Hipocampo/metabolismo , Humanos , Neurônios/metabolismo , Especificidade de Órgãos , Proteínas RGS/metabolismo , Roedores
4.
Biochemistry (Mosc) ; 86(6): 613-626, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34225586

RESUMO

Stress negatively affects processes of synaptic plasticity and is a major risk factor of various psychopathologies such as depression and anxiety. HOMER1 is an important component of the postsynaptic density: constitutively expressed long isoforms HOMER1b and HOMER1c bind to group I metabotropic glutamate receptors MGLUR1 (GRM1) and MGLUR5 and to other effector proteins, thereby forming a postsynaptic protein scaffold. Activation of the GLUR1-HOMER1b,c and/or GLUR5-HOMER1b,c complex regulates activity of the NMDA and AMPA receptors and Ca2+ homeostasis, thus modulating various types of synaptic plasticity. Dominant negative transcript Homer1a is formed as a result of activity-induced alternative termination of transcription. Expression of this truncated isoform in response to neuronal activation impairs interactions of HOMER1b,c with adaptor proteins, triggers ligand-independent signal transduction through MGLUR1 and/or MGLUR5, leads to suppression of the AMPA- and NMDA-mediated signal transmission, and thereby launches remodeling of the postsynaptic protein scaffold and inhibits long-term potentiation. The studies on animal models confirm that the HOMER1a-dependent remodeling most likely plays an important part in the stress susceptibility, whereas HOMER1a itself can be regarded as a neuroprotector. In this review article, we consider the effects of different stressors in various animal models on HOMER1 expression as well as impact of different HOMER1 variants on human behavior as well as structural and functional characteristics of the brain.


Assuntos
Proteínas de Arcabouço Homer/metabolismo , Plasticidade Neuronal , Neurônios/metabolismo , Animais , Proteínas de Arcabouço Homer/fisiologia , Humanos , Camundongos , Neurônios/fisiologia , Isoformas de Proteínas , Ratos , Receptor de Glutamato Metabotrópico 5/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Transdução de Sinais
5.
Biochemistry (Mosc) ; 86(6): 704-715, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34225593

RESUMO

Early-life stress is a risk factor for the development of behavioral and cognitive disorders in humans and animals. Such stressful situations include social isolation in early postnatal ontogenesis. Behavioral and cognitive impairments associated with neuroplastic changes in brain structures. We have found that after ten weeks of social isolation, male Wistar rats show behavioral abnormalities and cognitive deficit, accompanied by an increase in the relative expression of gene encoding serine protease prolyl endopeptidase (PREP, EC 3.4.21.26) in the brain frontal cortex. The present study aimed to assess synaptophysin (SYP), brain-derived neurotrophic factor precursor (proBDNF), and PREP expression using Western blot in the brain structures - the hippocampus, frontal cortex, and striatum of the rats subjected to prolonged social isolation compared with group-housed animals. Twenty Wistar rats were used for this study (10 males and 10 females). Experimental animals (5 males and 5 females) were kept one per cage for nine months, starting from the age of one month. Ten-month-old socially isolated rats showed memory deficit in passive avoidance paradigm and Morris Water Maze and reactivity to novelty reduction. We used monoclonal antibodies for the Western blot analysis of the expression of SYP, proBDNF, and PREP in the rat brain structures. Social isolation caused a proBDNF expression reduction in the frontal cortex in females and a reduction in PREP expression in the striatum in males. These data suppose that neurotrophic factors and PREP are involved in the mechanisms of behavioral and cognitive impairments observed in the rats subjected to prolonged social isolation with an early life onset.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Encéfalo/metabolismo , Prolil Oligopeptidases/genética , Isolamento Social , Estresse Psicológico/metabolismo , Animais , Feminino , Lobo Frontal/metabolismo , Regulação da Expressão Gênica , Hipocampo/metabolismo , Masculino , Plasticidade Neuronal , Ratos , Ratos Wistar , Estresse Psicológico/enzimologia , Estresse Psicológico/genética , Sinaptofisina/genética
6.
Int J Mol Sci ; 22(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198910

RESUMO

Changes in structural and functional neuroplasticity have been implicated in various neurological disorders. Sterol regulatory element-binding protein (SREBP)-1c is a critical regulatory molecule of lipid homeostasis in the brain. Recently, our findings have shown the potential involvement of SREBP-1c deficiency in the alteration of novel modulatory molecules in the hippocampus and occurrence of schizophrenia-like behaviors in mice. However, the possible underlying mechanisms, related to neuronal plasticity in the hippocampus, are yet to be elucidated. In this study, we investigated the hippocampus-dependent memory function and neuronal architecture of hippocampal neurons in SREBP-1c knockout (KO) mice. During the passive avoidance test, SREBP-1c KO mice showed memory impairment. Based on Golgi staining, the dendritic complexity, length, and branch points were significantly decreased in the apical cornu ammonis (CA) 1, CA3, and dentate gyrus (DG) subregions of the hippocampi of SREBP-1c KO mice, compared with those of wild-type (WT) mice. Additionally, significant decreases in the dendritic diameters were detected in the CA3 and DG subregions, and spine density was also significantly decreased in the apical CA3 subregion of the hippocampi of KO mice, compared with that of WT mice. Alterations in the proportions of stubby and thin-shaped dendritic spines were observed in the apical subcompartments of CA1 and CA3 in the hippocampi of KO mice. Furthermore, the corresponding differential decreases in the levels of SREBP-1 expression in the hippocampal subregions (particularly, a significant decrease in the level in the CA3) were detected by immunofluorescence. This study suggests that the contributions of SREBP-1c to the structural plasticity of the mouse hippocampus may have underlain the behavioral alterations. These findings offer insights into the critical role of SREBP-1c in hippocampal functioning in mice.


Assuntos
Espinhas Dendríticas/genética , Memória/fisiologia , Neurônios/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Animais , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/fisiologia , Espinhas Dendríticas/patologia , Regulação da Expressão Gênica/genética , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Camundongos , Camundongos Knockout , Plasticidade Neuronal/genética , Neurônios/patologia , Proteína de Ligação a Elemento Regulador de Esterol 1/deficiência
8.
Science ; 373(6550): 77-81, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34210880

RESUMO

Brain postnatal development is characterized by critical periods of experience-dependent remodeling of neuronal circuits. Failure to end these periods results in neurodevelopmental disorders. The cellular processes defining critical-period timing remain unclear. Here, we show that in the mouse visual cortex, astrocytes control critical-period closure. We uncover the underlying pathway, which involves astrocytic regulation of the extracellular matrix, allowing interneuron maturation. Unconventional astrocyte connexin signaling hinders expression of extracellular matrix-degrading enzyme matrix metalloproteinase 9 (MMP9) through RhoA-guanosine triphosphatase activation. Thus, astrocytes not only influence the activity of single synapses but also are key elements in the experience-dependent wiring of brain circuits.


Assuntos
Astrócitos/fisiologia , Período Crítico Psicológico , Plasticidade Neuronal , Córtex Visual/crescimento & desenvolvimento , Animais , Astrócitos/metabolismo , Conexina 30/metabolismo , Ativação Enzimática , GTP Fosfo-Hidrolases/metabolismo , Interneurônios/metabolismo , Interneurônios/fisiologia , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Sinapses/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
9.
FASEB J ; 35(8): e21726, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34196433

RESUMO

Increasing evidence shows that astrocytes, by releasing and uptaking neuroactive molecules, regulate synaptic plasticity, considered the neurophysiological basis of memory. This study investigated the impact of l-α-aminoadipate (l-AA) on astrocytes which sense and respond to stimuli at the synaptic level and modulate hippocampal long-term potentiation (LTP) and memory. l-AA selectivity toward astrocytes was proposed in the early 70's and further tested in different systems. Although it has been used for impairing the astrocytic function, its effects appear to be variable in different brain regions. To test the effects of l-AA in the hippocampus of male C57Bl/6 mice we performed two different treatments (ex vivo and in vivo) and took advantage of other compounds that were reported to affect astrocytes. l-AA superfusion did not affect the basal synaptic transmission but decreased LTP magnitude. Likewise, trifluoroacetate and dihydrokainate decreased LTP magnitude and occluded the effect of l-AA on synaptic plasticity, confirming l-AA selectivity. l-AA superfusion altered astrocyte morphology, increasing the length and complexity of their processes. In vivo, l-AA intracerebroventricular injection not only reduced the astrocytic markers but also LTP magnitude and impaired hippocampal-dependent memory in mice. Interestingly, d-serine administration recovered hippocampal LTP reduction triggered by l-AA (2 h exposure in hippocampal slices), whereas in mice injected with l-AA, the superfusion of d-serine did not fully rescue LTP magnitude. Overall, these data show that both l-AA treatments affect astrocytes differently, astrocytic activation or loss, with similar negative outcomes on hippocampal LTP, implying that opposite astrocytic adaptive alterations are equally detrimental for synaptic plasticity.


Assuntos
Ácido 2-Aminoadípico/toxicidade , Astrócitos/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Ácido 2-Aminoadípico/administração & dosagem , Ácido 2-Aminoadípico/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Animais , Astrócitos/patologia , Astrócitos/fisiologia , Células Cultivadas , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/toxicidade , Proteína Glial Fibrilar Ácida/metabolismo , Ácido Glutâmico/metabolismo , Hipocampo/patologia , Técnicas In Vitro , Injeções Intraventriculares , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Serina/administração & dosagem , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia
10.
Nat Commun ; 12(1): 4100, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215750

RESUMO

Tet3 is the main α-ketoglutarate (αKG)-dependent dioxygenase in neurons that converts 5-methyl-dC into 5-hydroxymethyl-dC and further on to 5-formyl- and 5-carboxy-dC. Neurons possess high levels of 5-hydroxymethyl-dC that further increase during neural activity to establish transcriptional plasticity required for learning and memory functions. How αKG, which is mainly generated in mitochondria as an intermediate of the tricarboxylic acid cycle, is made available in the nucleus has remained an unresolved question in the connection between metabolism and epigenetics. We show that in neurons the mitochondrial enzyme glutamate dehydrogenase, which converts glutamate into αKG in an NAD+-dependent manner, is redirected to the nucleus by the αKG-consumer protein Tet3, suggesting on-site production of αKG. Further, glutamate dehydrogenase has a stimulatory effect on Tet3 demethylation activity in neurons, and neuronal activation increases the levels of αKG. Overall, the glutamate dehydrogenase-Tet3 interaction might have a role in epigenetic changes during neural plasticity.


Assuntos
Núcleo Celular/enzimologia , Núcleo Celular/metabolismo , Dioxigenases/metabolismo , Glutamato Desidrogenase/metabolismo , Ácidos Cetoglutáricos/metabolismo , Neurônios/metabolismo , Animais , Encéfalo/metabolismo , Ciclo do Ácido Cítrico , Dioxigenases/genética , Epigenômica , Expressão Gênica , Glutamato Desidrogenase/genética , Ácido Glutâmico/metabolismo , Células HEK293 , Humanos , Complexo Cetoglutarato Desidrogenase/metabolismo , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Plasticidade Neuronal
11.
Artigo em Russo | MEDLINE | ID: mdl-34283538

RESUMO

The article discusses the pathogenetic and clinical features of tinnitus. It is emphasized that various causes contribute to the appearance of tinnitus, including somatic diseases, excess body weight, iatrogenies, otological diseases with an outcome in hearing loss. The anatomical and physiological features of the structure of the central part of the auditory system are considered. It is suggested that the occurrence of tinnitus is associated with the processes of maladaptive neuroplasticity caused by pathological changes in the neuronal activity of cortical structures of the CNS, and not with changes in the peripheral part of the auditory analyzer - the structures of the cochlea. The results of recent studies, including those using functional neuroimaging methods, indicate the significance of cortical connection disorders (human connectome) in patients with tinnitus. In patients with tinnitus, there are changes in regional neuronal activity and connections not only in the auditory cortex, but also in areas not directly related to the analysis of auditory afferentation. Thus, tinnitus can be considered as one of the variants of dysfunction of the human connectome, triggered primarily from the «auditory input¼.


Assuntos
Córtex Auditivo , Conectoma , Zumbido , Cóclea , Humanos , Plasticidade Neuronal , Zumbido/diagnóstico , Zumbido/etiologia
12.
Int J Mol Sci ; 22(11)2021 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-34204060

RESUMO

The establishment of neuronal circuits requires neurons to develop and maintain appropriate connections with cellular partners in and out the central nervous system. These phenomena include elaboration of dendritic arborization and formation of synaptic contacts, initially made in excess. Subsequently, refinement occurs, and pruning takes places both at axonal and synaptic level, defining a homeostatic balance maintained throughout the lifespan. All these events require genetic regulations which happens cell-autonomously and are strongly influenced by environmental factors. This review aims to discuss the involvement of guidance cues from the Semaphorin family.


Assuntos
Orientação de Axônios/fisiologia , Sinais (Psicologia) , Modelos Neurológicos , Neurônios/fisiologia , Semaforinas/metabolismo , Animais , Humanos , Plasticidade Neuronal/fisiologia
13.
eNeuro ; 8(3)2021.
Artigo em Inglês | MEDLINE | ID: mdl-34088737

RESUMO

Chronic vagus nerve stimulation (VNS) has been shown to facilitate learning, but effects of acute VNS on neural coding and behavior remain less well understood. Ferrets implanted with cuff electrodes on the vagus nerve were trained by classical conditioning on an auditory tone frequency-reward association. One tone was associated with reward while another tone was not. Tone frequencies and reward associations were changed every 2 d, requiring learning of a new relationship. When tones were paired with VNS, animals consistently learned the new association within 2 d. When VNS occurred randomly between trials, learning within 2 d was unreliable. In passively listening animals, neural activity in primary auditory cortex (A1) and pupil size were recorded before and after acute VNS-tone pairing. After pairing with a neuron's best-frequency (BF) tone, responses by a subpopulation of neurons were reduced. VNS paired with an off-BF tone or during intertrial intervals had no effect. The BF-specific reduction in neural responses after VNS remained, even after regressing out changes explained by pupil-indexed arousal. VNS induced brief dilation in the pupil, and the size of this change predicted the magnitude of persistent changes in the neural response. This interaction suggests that fluctuations in neuromodulation associated with arousal gate the long-term VNS effects on neural activity.


Assuntos
Córtex Auditivo , Estimulação do Nervo Vago , Animais , Percepção Auditiva , Plasticidade Neuronal , Ratos , Ratos Sprague-Dawley , Nervo Vago
14.
Small ; 17(26): e2101100, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34081416

RESUMO

Multiple studies have reported the observation of electro-synaptic response in different metal/insulator/metal devices. However, most of them analyzed large (>1 µm2 ) devices that do not meet the integration density required by industry (1010  devices/mm2 ). Some studies emploied a scanning tunneling microscope (STM) to explore nano-synaptic response in different materials, but in this setup there is a nanogap between the insulator and one of the metallic electrodes (i.e., the STM tip), not present in real devices. Here, it is demonstrated how to use conductive atomic force microscopy to explore the presence and quality of nano-synaptic response in confined areas <50 nm2 . Graphene oxide (GO) is selected due to its easy fabrication. Metal/GO/metal nano-synapses exhibit potentiation and paired pulse facilitation with low write current levels <1 µA (i.e., power consumption ≈3 µW), controllable excitatory post-synaptic currents, and long-term potentiation and depression. The results provide a new method to explore nano-synaptic plasticity at the nanoscale, and point to GO as an important candidate for the fabrication of ultrasmall (<50 nm2 ) electronic synapses fulfilling the integration density requirements of neuromorphic systems.


Assuntos
Grafite , Sinapses , Microscopia de Força Atômica , Plasticidade Neuronal
15.
J Cell Sci ; 134(12)2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34137444

RESUMO

Nervous system development and plasticity involve changes in cellular morphology, making morphological analysis a valuable exercise in the study of nervous system development, function and disease. Morphological analysis is a time-consuming exercise requiring meticulous manual tracing of cellular contours and extensions. We have developed a software tool, called SMorph, to rapidly analyze the morphology of cells of the nervous system. SMorph performs completely automated Sholl analysis. It extracts 23 morphometric features based on cell images and Sholl analysis parameters, followed by principal component analysis (PCA). SMorph was tested on neurons, astrocytes and microglia and reveals subtle changes in cell morphology. Using SMorph, we found that chronic 21-day treatment with the antidepressant desipramine results in a significant structural remodeling in hippocampal astrocytes in mice. Given the proposed involvement of astroglial structural changes and atrophy in major depression in humans, our results reveal a novel kind of structural plasticity induced by chronic antidepressant administration.


Assuntos
Astrócitos , Hipocampo , Animais , Antidepressivos/farmacologia , Camundongos , Plasticidade Neuronal , Neurônios , Software
16.
Artigo em Russo | MEDLINE | ID: mdl-34184494

RESUMO

The process of balance restoration in patients with the vestibular disorders is known as «vestibular compensation¼. It is obvious nowadays that this phenomenon is very complex and is associated with the deep brain neuroplastic changes involving reinnervation, habituation and adaptation. The research of the last decades has shown some fundamental physiologic mechanisms that form the basis of neuroplasticity, establish the staging of ongoing transformations and analyze the opportunity to improve and/or accelerate vestibular compensation with the help of vestibular rehabilitation and contemporary medications such as betaserc long.


Assuntos
Doenças Vestibulares , Vestíbulo do Labirinto , Adaptação Fisiológica , Humanos , Plasticidade Neuronal , Vertigem
17.
Int J Mol Sci ; 22(9)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062742

RESUMO

Acid-sensing ion channels (ASICs) are mainly proton-gated cation channels that are activated by pH drops and nonproton ligands. They are part of the degenerin/epithelial sodium channel superfamily due to their sodium permeability. Predominantly expressed in the central nervous system, ASICs are involved in synaptic plasticity, learning/memory, and fear conditioning. These channels have also been implicated in multiple disease conditions, including ischemic brain injury, multiple sclerosis, Alzheimer's disease, and drug addiction. Recent research has illustrated the involvement of ASICs in mechanosensation. Mechanosensation is a form of signal transduction in which mechanical forces are converted into neuronal signals. Specific mechanosensitive functions have been elucidated in functional ASIC1a, ASIC1b, ASIC2a, and ASIC3. The implications of mechanosensation in ASICs indicate their subsequent involvement in functions such as maintaining blood pressure, modulating the gastrointestinal function, and bladder micturition, and contributing to nociception. The underlying mechanism of ASIC mechanosensation is the tether-gate model, which uses a gating-spring mechanism to activate ASIC responses. Further understanding of the mechanism of ASICs will help in treatments for ASIC-related pathologies. Along with the well-known chemosensitive functions of ASICs, emerging evidence has revealed that mechanosensitive functions of ASICs are important for maintaining homeostasis and contribute to various disease conditions.


Assuntos
Canais Iônicos Sensíveis a Ácido/genética , Canais de Sódio Degenerina/genética , Mecanotransdução Celular/genética , Neurônios/metabolismo , Canais Iônicos Sensíveis a Ácido/metabolismo , Animais , Canais de Sódio Degenerina/metabolismo , Humanos , Esclerose Múltipla/genética , Esclerose Múltipla/patologia , Plasticidade Neuronal , Sódio/metabolismo
18.
Nat Commun ; 12(1): 3558, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34117238

RESUMO

Hippocampal place cells contribute to mammalian spatial navigation and memory formation. Numerous models have been proposed to explain the location-specific firing of this cognitive representation, but the pattern of excitatory synaptic input leading to place firing is unknown, leaving no synaptic-scale explanation of place coding. Here we used resonant scanning two-photon microscopy to establish the pattern of synaptic glutamate input received by CA1 place cells in behaving mice. During traversals of the somatic place field, we found increased excitatory dendritic input, mainly arising from inputs with spatial tuning overlapping the somatic field, and functional clustering of this input along the dendrites over ~10 µm. These results implicate increases in total excitatory input and co-activation of anatomically clustered synaptic input in place firing. Since they largely inherit their fields from upstream synaptic partners with similar fields, many CA1 place cells appear to be part of multi-brain-region cell assemblies forming representations of specific locations.


Assuntos
Hipocampo/fisiologia , Células de Lugar/fisiologia , Memória Espacial/fisiologia , Sinapses/fisiologia , Potenciais de Ação/fisiologia , Animais , Comportamento Animal , Região CA1 Hipocampal , Dendritos/fisiologia , Ácido Glutâmico , Hipocampo/diagnóstico por imagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Plasticidade Neuronal/fisiologia , Neurotransmissores
19.
Nat Commun ; 12(1): 3915, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34168140

RESUMO

Memory is supported by a specific collection of neurons distributed in broad brain areas, an engram. Despite recent advances in identifying an engram, how the engram is created during memory formation remains elusive. To explore the relation between a specific pattern of input activity and memory allocation, here we target a sparse subset of neurons in the auditory cortex and thalamus. The synaptic inputs from these neurons to the lateral amygdala (LA) are not potentiated by fear conditioning. Using an optogenetic priming stimulus, we manipulate these synapses to be potentiated by the learning. In this condition, fear memory is preferentially encoded in the manipulated cell ensembles. This change, however, is abolished with optical long-term depression (LTD) delivered shortly after training. Conversely, delivering optical long-term potentiation (LTP) alone shortly after fear conditioning is sufficient to induce the preferential memory encoding. These results suggest a synaptic plasticity-dependent competition rule underlying memory formation.


Assuntos
Memória/fisiologia , Plasticidade Neuronal/fisiologia , Animais , Complexo Nuclear Basolateral da Amígdala/fisiologia , Encéfalo/citologia , Encéfalo/fisiologia , Condicionamento Clássico/fisiologia , Potenciais Evocados Auditivos , Medo/fisiologia , Halorrodopsinas/genética , Halorrodopsinas/metabolismo , Aprendizagem/fisiologia , Potenciação de Longa Duração/fisiologia , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Optogenética
20.
Life Sci ; 279: 119707, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34102195

RESUMO

AIMS: The present study investigated if treatment with the immunotherapeutic, lacto-N-fucopentaose-III (LNFPIII), resulted in amelioration of acute and persisting deficits in synaptic plasticity and transmission as well as trophic factor expression along the hippocampal dorsoventral axis in a mouse model of Gulf War Illness (GWI). MAIN METHODS: Mice received either coadministered or delayed LNFPIII treatment throughout or following, respectively, exposure to a 15-day GWI induction paradigm. Subsets of animals were subsequently sacrificed 48 h, seven months, or 11 months post GWI-related (GWIR) exposure for hippocampal qPCR or in vitro electrophysiology experiments. KEY FINDINGS: Progressively worsened impairments in hippocampal synaptic plasticity, as well as a biphasic effect on hippocampal synaptic transmission, were detected in GWIR-exposed animals. Dorsoventral-specific impairments in hippocampal synaptic responses became more pronounced over time, particularly in the dorsal hippocampus. Notably, delayed LNFPIII treatment ameliorated GWI-related aberrations in hippocampal synaptic plasticity and transmission seven and 11 months post-exposure, an effect that was consistent with enhanced hippocampal trophic factor expression and absence of increased interleukin 6 (IL-6) in animals treated with LNFPIII. SIGNIFICANCE: Approximately a third of Gulf War Veterans have GWI; however, GWI therapeutics are presently limited to targeted and symptomatic treatments. As increasing evidence underscores the substantial role of persisting neuroimmune dysfunction in GWI, efficacious neuroactive immunotherapeutics hold substantial promise in yielding GWI remission. The findings in the present report indicate that LNFPIII may be an efficacious candidate for ameliorating persisting neurological abnormalities presented in GWI.


Assuntos
Amino Açúcares/farmacologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Síndrome do Golfo Pérsico/prevenção & controle , Polissacarídeos/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Síndrome do Golfo Pérsico/etiologia , Síndrome do Golfo Pérsico/patologia
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