Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 44.258
Filtrar
1.
J Toxicol Sci ; 47(1): 31-37, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34987139

RESUMO

Brain susceptibility to methylmercury (MeHg) is developmentally and regionally specific in both humans and rodents, but the mechanism is not well clarified. Reactive sulfur species (RSS) with high nucleophilicity can react with MeHg, leading to the formation of a less toxic metabolite bismethylmercury sulfide, thus exerting cytoprotection. In this study, we assessed the variation of RSS content in the rat brain and evaluated its relevance in sensitivity to MeHg. Analyses of fetal/juvenile rat brains showed low RSS levels in early developmental stages. Site-specific analysis of adult rat brains revealed that cerebellar RSS levels were lower than those of the hippocampus. Microscopically, RSS levels of the granular cell layer were lower than those of the molecular layer in the cerebellum. Thus, low RSS levels corresponded with age and site of the brain that is vulnerable to MeHg. Taken together with the finding that brain RSS were consumed during MeHg exposure, these results indicate that RSS is a factor that defines the specificity of MeHg vulnerability in the brain.


Assuntos
Compostos de Metilmercúrio , Animais , Encéfalo , Cerebelo , Compostos de Metilmercúrio/toxicidade , Ratos , Sulfetos , Enxofre
2.
Eur Radiol ; 32(1): 300-307, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34189601

RESUMO

OBJECTIVES: Crossed cerebro-cerebellar BOLD activations have recently come to light as additional diagnostic features for patients with brain tumors. The covert verb generation (VG) task is a widely used language paradigm to determine these language-related crossed activations. Here we demonstrate these crossed activations in two additional language paradigms, the semantic and phonological association tasks. We propose the merit of these tasks to language lateralization determination in the clinic as they are easy to monitor and suitable for patients with aphasia. METHODS: Patients with brain tumors localized at different cortical sites (n = 71) performed three language paradigms, namely the VG task as well as the semantic (SA) and phonological (PA) association tasks with button-press responses. Respective language activations in disparate cortical regions and the cerebellum were assigned laterality. Agreements in laterality between the two new tasks and the verb generation task were tested using Cohen's kappa. RESULTS: Both tasks significantly agreed in cortical and cerebellar lateralization with the verb generation task in patients. Additionally, a McNemar test confirmed the presence of crossed activations in the cortex and the cerebellum in the entire subject population. CONCLUSION: We demonstrated that the semantic and phonological association tasks resulted in crossed cerebro-cerebellar language lateralization activations as those observed due to the covert verb generation task. This may suggest the possibility of these tasks being used conjointly with the traditional verb generation task, especially for subjects that may be unable to perform the latter. KEY POINTS: • The semantic and phonological association tasks can be useful as additional presurgical fMRI language lateralization paradigms for brain tumor patients along with the standard verb generation task. • All three tasks also confirm the presence of crossed cerebro-cerebellar language activations in the current subject population.


Assuntos
Neoplasias Encefálicas , Idioma , Mapeamento Encefálico , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética
3.
Ultrasonics ; 119: 106601, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34624581

RESUMO

Herein, we propose a method to estimate the reflection coefficient of the ultrasonic wave transmitted onto an object and to display this with acoustic impedance distribution. The observation targets were glial cells, which have a rigid cytoskeleton and spread out well on a culture substrate. A reflection coefficient derived only from the cells was then obtained using a deconvolution process. In the conventional method, the deconvolution process that was performed only in the frequency domain would cause an error in the reconstructed signal, and it formed an artifact when the result was converted into the acoustic impedance image. To solve this problem, two types of deconvolution techniques were applied in either the full frequency or time-frequency domain. The results of both methods were then compared. Since the characteristic acoustic impedance is a physical property substantially equivalent to the bulk modulus, it can be considered that the internal elastic parameter is thus estimated. An analysis of the nucleus based on its position in the acoustic impedance image was then performed. The results indicated that the proposed time-frequency domain deconvolution method is able to maintain the structure of the cell, while the cell itself is free from unwanted artifacts. The nucleus was also estimated to be located toward the center of the cell, with lower acoustic impedance value than the cytoskeleton. The results of this study could contribute to establishing a method for monitoring the internal condition of cultured cells in regenerative medicine and drug discovery.


Assuntos
Microscopia Acústica/métodos , Neuroglia/ultraestrutura , Animais , Células Cultivadas , Cerebelo/citologia , Análise dos Mínimos Quadrados , Ratos , Transdutores
4.
Gene ; 809: 146001, 2022 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-34637898

RESUMO

The function of the Agtpbp1 gene has mainly been delineated by studying Agtpbp1pcd (pcd) mutant mice, characterized by losses in cerebellar Purkinje and granule cells along with degeneration of retinal photoreceptors, mitral cells of the olfactory bulb, thalamic neurons, and alpha-motoneurons. As a result of cerebellar degeneration, cerebellar GABA and glutamate concentrations in Agtpbp1pcd mutants decreased while monoamine concentrations increased. The salient behavioral phenotypes include cerebellar ataxia, a loss in motor coordination, and cognitive deficits. Similar neuropathogical and behavioral profiles have been described in childhood-onset human subjects with biallelic variants of AGTPBP1, including cerebellar ataxia and hypotonia.


Assuntos
Cerebelo/fisiologia , Proteínas de Ligação ao GTP/genética , Doenças Neurodegenerativas/patologia , D-Ala-D-Ala Carboxipeptidase Tipo Serina/genética , Animais , Cerebelo/citologia , Cricetinae , Proteínas de Ligação ao GTP/metabolismo , Humanos , Camundongos Mutantes , Doenças Neurodegenerativas/genética , Células de Purkinje/patologia , Células de Purkinje/fisiologia , D-Ala-D-Ala Carboxipeptidase Tipo Serina/metabolismo , Ovinos
5.
Neural Netw ; 146: 316-333, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34923219

RESUMO

The vestibulo-ocular reflex (VOR) stabilizes vision during head motion. Age-related changes of vestibular neuroanatomical properties predict a linear decay of VOR function. Nonetheless, human epidemiological data show a stable VOR function across the life span. In this study, we model cerebellum-dependent VOR adaptation to relate structural and functional changes throughout aging. We consider three neurosynaptic factors that may codetermine VOR adaptation during aging: the electrical coupling of inferior olive neurons, the long-term spike timing-dependent plasticity at parallel fiber - Purkinje cell synapses and mossy fiber - medial vestibular nuclei synapses, and the intrinsic plasticity of Purkinje cell synapses Our cross-sectional aging analyses suggest that long-term plasticity acts as a global homeostatic mechanism that underpins the stable temporal profile of VOR function. The results also suggest that the intrinsic plasticity of Purkinje cell synapses operates as a local homeostatic mechanism that further sustains the VOR at older ages. Importantly, the computational epidemiology approach presented in this study allows discrepancies among human cross-sectional studies to be understood in terms of interindividual variability in older individuals. Finally, our longitudinal aging simulations show that the amount of residual fibers coding for the peak and trough of the VOR cycle constitutes a predictive hallmark of VOR trajectories over a lifetime.


Assuntos
Adaptação Fisiológica , Reflexo Vestíbulo-Ocular , Idoso , Envelhecimento , Cerebelo , Estudos Transversais , Humanos , Pessoa de Meia-Idade , Células de Purkinje
6.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(12): 1250-1255, 2021 Dec 15.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34911608

RESUMO

OBJECTIVES: To study the changes in biochemical metabolites in the thalamus and the cerebellum and their association with clinical features in children with autism spectrum disorder (ASD). METHODS: In this prospective study, magnetic resonance spectroscopy (MRS) with point-resolved spatial selection was used to analyze the thalamus and the cerebellum at both sides in 50 children with ASD aged 2-6 years. Creatine (Cr) was as the internal standard to measure the relative values of N-acetylaspartate (NAA)/Cr, choline (Cho)/Cr, myoinositol (MI)/Cr, and glutamine and glutamate complex (Glx)/Cr, and the differences in metabolites and their association with clinical symptoms were compared. RESULTS: In the children with ASD, NAA/Cr in the left thalamus was positively correlated with the scores of hearing-language and hand-eye coordination in the Griffiths Development Scales-Chinese (P<0.05). Cho/Cr in the right cerebellum was positively correlated with the scores of personal-social competence, hearing-language, and hand-eye coordination (P<0.05). NAA/Cr and Glx/Cr in the left thalamus were positively correlated with those in the left cerebellum (P<0.05). There was no significant difference in metabolites between the left and right sides of the thalamus and the cerebellum in the children with ASD (P>0.05). CONCLUSIONS: There are metabolic disorders in the cerebellum and the thalamus in children with ASD, and there is a correlation between the changes of metabolites in the left cerebellum and the left thalamus. Some metabolic indexes are related to the clinical symptoms of ASD. MRS may reveal the pathological basis of ASD and provide a basis for diagnosis and prognosis assessment of ASD as a noninvasive and quantitative detection method.


Assuntos
Transtorno do Espectro Autista , Transtorno do Espectro Autista/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Criança , Colina , Humanos , Espectroscopia de Ressonância Magnética , Estudos Prospectivos , Tálamo/diagnóstico por imagem
7.
Int J Mol Sci ; 22(24)2021 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-34948305

RESUMO

Radial glial cells are a distinct non-neuronal cell type that, during development, span the entire width of the brain walls of the ventricular system. They play a central role in the origin and placement of neurons, since their processes form structural scaffolds that guide and facilitate neuronal migration. Furthermore, glutamatergic signaling in the radial glia of the adult cerebellum (i.e., Bergmann glia), is crucial for precise motor coordination. Radial glial cells exhibit spontaneous calcium activity and functional coupling spread calcium waves. However, the origin of calcium activity in relation to the ontogeny of cerebellar radial glia has not been widely explored, and many questions remain unanswered regarding the role of radial glia in brain development in health and disease. In this study we used a combination of whole mount immunofluorescence and calcium imaging in transgenic (gfap-GCaMP6s) zebrafish to determine how development of calcium activity is related to morphological changes of the cerebellum. We found that the morphological changes in cerebellar radial glia are quite dynamic; the cells are remarkably larger and more elaborate in their soma size, process length and numbers after 7 days post fertilization. Spontaneous calcium events were scarce during the first 3 days of development and calcium waves appeared on day 5, which is associated with the onset of more complex morphologies of radial glia. Blockage of gap junction coupling inhibited the propagation of calcium waves, but not basal local calcium activity. This work establishes crucial clues in radial glia organization, morphology and calcium signaling during development and provides insight into its role in complex behavioral paradigms.


Assuntos
Sinalização do Cálcio/fisiologia , Cerebelo/metabolismo , Cerebelo/fisiologia , Neuroglia/metabolismo , Neuroglia/fisiologia , Peixe-Zebra/metabolismo , Peixe-Zebra/fisiologia , Animais , Animais Geneticamente Modificados/metabolismo , Animais Geneticamente Modificados/fisiologia , Cálcio/metabolismo , Neurogênese/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(12): 1211-1215, 2021 Dec 10.
Artigo em Chinês | MEDLINE | ID: mdl-34839509

RESUMO

OBJECTIVE: To explore the pathogenesis of two siblings (including a fetus) from a pedigree affected with Joubert syndrome. METHODS: Peripheral blood samples of the proband and his parents as well as amniotic fluid and abortion tissues of the fetus were collected. Part of the samples were used for the extraction of DNA, and whole exome sequencing (WES) was carried out to screen potential variants in the proband and his parents. Suspected variants were subjected to bioinformatics analysis with consideration of the clinical phenotype, and were verified by Sanger sequencing of the proband, fetus and their parents.The remainders were used for the extraction of RNA, and the mechanism of splicing variant was validated by reverse transcription-PCR (RT-PCR). RESULTS: WES showed that both patients have carried c.175C>T (p.R59X) and c.553+1G>A compound heterozygous variants of the TMEM237 gene. Among these, c.175C>T was a nonsense mutation inherited from the asymptomatic mother, while c.553+1G>A was an alternative splicing mutation inherited from the asymptomatic father. RT-PCR showed that this variant has resulted in aberrant splicing by exon skipping. CONCLUSION: The compound heterozygous variants of the TMEM237 gene probably underlay the etiology of Joubert syndrome in this pedigree. Above finding has enriched the phenotype and variant spectrum of the TMEM237 gene, and facilitated genetic counseling and prenatal diagnosis for the family.


Assuntos
Anormalidades Múltiplas , Anormalidades do Olho , Doenças Renais Císticas , Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Feminino , Genótipo , Humanos , Mutação , Linhagem , Fenótipo , Gravidez , Retina/anormalidades
9.
Klin Monbl Augenheilkd ; 238(11): 1186-1195, 2021 Nov.
Artigo em Inglês, Alemão | MEDLINE | ID: mdl-34784642

RESUMO

Nystagmus is defined as rhythmic, most often involuntary eye movements. It normally consists of a slow (pathological) drift of the eyes, followed by a fast central compensatory movement back to the primary position (refixation saccade). The direction, however, is reported according to the fast phase. The cardinal symptoms are, on the one hand, blurred vision, jumping images (oscillopsia), reduced visual acuity and, sometimes, double vision; many of these symptoms depend on the eye position. On the other hand, depending on the etiology, patients may suffer from the following symptoms: 1. permanent dizziness, postural imbalance, and gait disorder (typical of downbeat and upbeat nystagmus); 2. if the onset of symptoms is acute, the patient may experience spinning vertigo with a tendency to fall to one side (due to ischemia in the area of the brainstem or cerebellum with central fixation nystagmus or as acute unilateral vestibulopathy with spontaneous peripheral vestibular nystagmus); or 3. positional vertigo. There are two major categories: the first is spontaneous nystagmus, i.e., nystagmus which occurs in the primary position as upbeat or downbeat nystagmus; and the second includes various types of nystagmus which are induced or modified by certain factors. Examples are gaze-evoked nystagmus, head-shaking nystagmus, positional nystagmus, and hyperventilation-induced nystagmus. In addition, there are disorders similar to nystagmus, such as ocular flutter or opsoclonus. The most common central types of spontaneous nystagmus are downbeat and upbeat, infantile, pure torsional, pendular fixation, periodic alternating, and seesaw nystagmus. Many types of nystagmus allow a precise neuroanatomical localization: for instance, downbeat nystagmus, which is most often caused by a bilateral floccular lesion or dysfunction, or upbeat nystagmus, which is caused by a lesion in the midbrain or medulla. Examples of drug treatment are the use of 4-aminopyridine for downbeat and upbeat nystagmus, memantine or gabapentin for pendular fixation nystagmus, or baclofen for periodic alternating nystagmus. In this article we are focusing on nystagmus. In a second article we will focus on central ocular motor disorders, such as saccade or gaze palsy, internuclear ophthalmoplegia, and gaze-holding deficits. Therefore, these types of eye movements will not be described here in detail.


Assuntos
Nistagmo Patológico , Transtornos da Motilidade Ocular , Cerebelo , Movimentos Oculares , Humanos , Nistagmo Patológico/diagnóstico , Movimentos Sacádicos
10.
Am J Case Rep ; 22: e933995, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34776506

RESUMO

BACKGROUND Multiple system atrophy cerebellar type (MSA-C) is a subtype of MSA that presents with predominant ataxia along with lesser signs of parkinsonism and autonomic dysfunction. Previous studies have shown benefits from carbidopa/levodopa therapy for the MSA parkinsonian subtype but few studies have focused on the MSA-C subtype. We present a video case of MSA-C that demonstrated significant improvement with carbidopa/levodopa therapy. CASE REPORT A right-handed 61-year-old man with a past medical history of chronic microvascular ischemia, mild lower extremity neuropathy, and lumbar and cervical stenosis status after decompression presented with progressive worsening gait changes over several months with acute deterioration before admission. The initial neurological workup demonstrated bilateral cogwheel rigidity; difficulty with movement initiation. including standing up from a seated position; slow saccadic eye movements; masked facies (hypomimia); right ankle clonus; bilateral upper and left lower limb ataxia; and hyperreflexia. A follow-up workup was negative for metabolic, infectious, and paraneoplastic causes, but magnetic resonance imaging demonstrated cerebellar atrophy along with a "hot cross bun sign" suggestive of probable MSA-C according to consensus criteria, and the patient was started on carbidopa-levodopa. He subsequently demonstrated improvement in key motor domains, including his cogwheel rigidity and gait testing, and was discharged shortly thereafter. CONCLUSIONS Through this case report, we highlight a significant response to L-dopa therapy beyond what is normally expected according to diagnostic criteria for MSA. MSA treatment responsiveness can vary significantly across patients, which warrants additional studies into appropriate treatment choices for patients with Parkinson's disease and MSA.


Assuntos
Atrofia de Múltiplos Sistemas , Doença de Parkinson , Transtornos Parkinsonianos , Cerebelo , Dopamina , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/diagnóstico , Atrofia de Múltiplos Sistemas/tratamento farmacológico
11.
Neurol India ; 69(5): 1318-1325, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34747805

RESUMO

Introduction: Genetically defined spinocerebellar ataxia (SCA) type 1 and 2 patients have differential clinical profile along with probable distinctive cortical and subcortical neurodegeneration. We compared the degree of brain atrophy in the two subtypes with their phenotypic and genotypic parameters. Methods: MRI was performed using a 3T scanner (Philips, Achieva) to obtain 3D T1-weighted scans of the whole brain and analyzed by FreeSurfer (version 5.3 and 6 dev.) software. Genetically proven SCA1 (n = 18) and SCA2 (n = 25) patients with age-matched healthy controls (n = 8) were recruited. Clinical severity was assessed by the International Cooperative Ataxia Rating Scale (ICARS). To know the differential pattern of atrophy, the groups were compared using ANOVA/Kruskal-Wallis test and followed by correlation analysis with multiple corrections. Further, machine learning-based classification of SCA subtypes was carried out. Result: We found (i) bilateral frontal, parietal, temporal, and occipital atrophy in SCA1 and SCA2 patients; (ii) reduced volume of cerebellum, regions of brain stem, basal ganglia along with the certain subcortical areas such as hippocampus, amygdala, thalamus, diencephalon, and corpus callosum in SCA1 and SCA2 subtypes; (iii) higher subcortical atrophy SCA2 than SCA1 (iv) correlation between brain atrophy and disease attributes; (v) differential predictive pattern of two SCA subtypes using machine learning approach. Conclusion: The present study suggests that SCA1 and SCA2 do not differ in cortical thinning while a characteristic pattern of subcortical atrophy SCA2 > SCA1 is observed along with correlation of brain atrophy and disease attributes. This may provide the diagnostic guidance of MRI to SCA subtypes and differential therapies.


Assuntos
Ataxias Espinocerebelares , Atrofia/patologia , Encéfalo/diagnóstico por imagem , Cerebelo/patologia , Humanos , Imageamento por Ressonância Magnética , Ataxias Espinocerebelares/diagnóstico por imagem
12.
Acta Clin Croat ; 60(2): 304-308, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34744282

RESUMO

We present a case of a patient with treatment resistant hallucinatory experiences with incidental finding of an arachnoid cyst localized in the posterior infratentorial cranial fossa dorsally to the cerebellum. Psychological testing revealed significant deficit of cognitive functions to the level of mild intellectual disability in a person that had previously finished high school with good grades. A combination of clozapine and lamotrigine led to significant improvement in mood and reduction of hallucinations, but without improvement in cognitive functions. We also performed a literature review of previously published case reports or case series of co-occurring posterior fossa arachnoid cyst and schizophrenia or psychosis or psychiatric symptoms using PubMed search and discuss some controversies considering their treatment outcome.


Assuntos
Cistos Aracnóideos , Transtornos Psicóticos , Cistos Aracnóideos/complicações , Cistos Aracnóideos/diagnóstico por imagem , Cerebelo , Cognição , Fossa Craniana Posterior , Humanos , Imageamento por Ressonância Magnética , Transtornos Psicóticos/etiologia
13.
Elife ; 102021 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-34730085

RESUMO

Synaptic transmission, connectivity, and dendritic morphology mature in parallel during brain development and are often disrupted in neurodevelopmental disorders. Yet how these changes influence the neuronal computations necessary for normal brain function are not well understood. To identify cellular mechanisms underlying the maturation of synaptic integration in interneurons, we combined patch-clamp recordings of excitatory inputs in mouse cerebellar stellate cells (SCs), three-dimensional reconstruction of SC morphology with excitatory synapse location, and biophysical modeling. We found that postnatal maturation of postsynaptic strength was homogeneously reduced along the somatodendritic axis, but dendritic integration was always sublinear. However, dendritic branching increased without changes in synapse density, leading to a substantial gain in distal inputs. Thus, changes in synapse distribution, rather than dendrite cable properties, are the dominant mechanism underlying the maturation of neuronal computation. These mechanisms favor the emergence of a spatially compartmentalized two-stage integration model promoting location-dependent integration within dendritic subunits.


Assuntos
Cerebelo/fisiologia , Interneurônios/fisiologia , Transmissão Sináptica/fisiologia , Animais , Cerebelo/crescimento & desenvolvimento , Feminino , Interneurônios/metabolismo , Masculino , Camundongos
14.
Neurosci Bull ; 37(11): 1529-1541, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34609736

RESUMO

The cerebellum is conceptualized as a processor of complex movements and is also endowed with roles in cognitive and emotional behaviors. Although the axons of deep cerebellar nuclei are known to project to primary thalamic nuclei, macroscopic investigation of the characteristics of these projections, such as the spatial distribution of recipient zones, is lacking. Here, we studied the output of the cerebellar interposed nucleus (IpN) to the ventrolateral (VL) and centrolateral (CL) thalamic nuclei using electrophysiological recording in vivo and trans-synaptic viral tracing. We found that IpN stimulation induced mono-synaptic evoked potentials (EPs) in the VL but not the CL region. Furthermore, both the EPs induced by the IpN and the innervation of IpN projections displayed substantial heterogeneity across the VL region in three-dimensional space. These findings indicate that the recipient zones of IpN inputs vary between and within thalamic nuclei and may differentially control thalamo-cortical networks.


Assuntos
Núcleos Cerebelares , Núcleos Talâmicos , Axônios , Cerebelo
15.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(10): 985-988, 2021 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-34625938

RESUMO

OBJECTIVE: To analyze the clinical phenotype and pathogenic variant in a child diagnosed with mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH). METHODS: Clinical phenotype of the child was reviewed. Whole exome sequencing was carried out for the child. Candidate variant was verified by Sanger sequencing of the family member. RESULTS: The proband manifested dyskinesia, development delay, cerebellar hypoplasia and bilateral hearing impairment. WES results revealed that the proband has carried a pathogenic c.1641_1644delACAA (p.Thr548Trpfs*69) variant of the CASK gene, which was verified by Sanger sequencing to be a de novo variant. CONCLUSION: The c.1641_1644delACAA (p.Thr548Trpfs*69) variant of the CASK gene probably underlay the MICPCH in the proband. Above finding has provided a basis for genetic counseling. WES should be considered for the diagnosis of neurological dysplasia.


Assuntos
Microcefalia , Malformações do Sistema Nervoso , Cerebelo/anormalidades , Criança , Deficiências do Desenvolvimento , Família , Humanos , Retardo Mental Ligado ao Cromossomo X , Microcefalia/genética
16.
Elife ; 102021 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-34612812

RESUMO

The Ca2+-dependence of the priming, fusion, and replenishment of synaptic vesicles are fundamental parameters controlling neurotransmitter release and synaptic plasticity. Despite intense efforts, these important steps in the synaptic vesicles' cycle remain poorly understood due to the technical challenge in disentangling vesicle priming, fusion, and replenishment. Here, we investigated the Ca2+-sensitivity of these steps at mossy fiber synapses in the rodent cerebellum, which are characterized by fast vesicle replenishment mediating high-frequency signaling. We found that the basal free Ca2+ concentration (<200 nM) critically controls action potential-evoked release, indicating a high-affinity Ca2+ sensor for vesicle priming. Ca2+ uncaging experiments revealed a surprisingly shallow and non-saturating relationship between release rate and intracellular Ca2+ concentration up to 50 µM. The rate of vesicle replenishment during sustained elevated intracellular Ca2+ concentration exhibited little Ca2+-dependence. Finally, quantitative mechanistic release schemes with five Ca2+ binding steps incorporating rapid vesicle replenishment via parallel or sequential vesicle pools could explain our data. We thus show that co-existing high- and low-affinity Ca2+ sensors mediate priming, fusion, and replenishment of synaptic vesicles at a high-fidelity synapse.


Assuntos
Cálcio/metabolismo , Neurotransmissores/metabolismo , Sinapses/metabolismo , Animais , Transporte Biológico , Cerebelo/citologia , Cerebelo/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Transmissão Sináptica , Vesículas Sinápticas/metabolismo
17.
Eur J Neurosci ; 54(9): 7048-7062, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34622493

RESUMO

Calcium influx into presynaptic terminals through voltage-gated Ca2+ channels triggers univesicular or multivesicular release of neurotransmitters depending on the characteristics of the release machinery. However, the mechanisms underlying multivesicular release (MVR) and its regulation remain unclear. Previous studies showed that in rat cerebellum, the cyclin-dependent kinase inhibitor roscovitine profoundly increases excitatory postsynaptic current (EPSC) amplitudes at granule cell (GC)-Purkinje cell (PC) synapses by enhancing the MVR of glutamate. This compound can also moderately augment the amplitude and prolong the decay time of inhibitory postsynaptic currents (IPSCs) at molecular layer interneuron (MLI)-PC synapses via MVR enhancement and GABA spillover, thus allowing for persistent activation of perisynaptic GABA receptors. The enhanced MVR may depend on the driving force for Cav 2.1 channel-mediated Ca2+ influx. To determine whether the distinct spatiotemporal dynamics of presynaptic Ca2+ influence MVR, we compared the effects of slow and fast Ca2+ chelators, that is, EGTA and BAPTA, respectively, on roscovitine-induced actions at GC-PC and MLI-PC synapses. Membrane-permeable EGTA-AM decreased GC-PC EPSC and MLI-PC IPSC amplitudes to a similar extent but suppressed the roscovitine-induced enhancement of EPSCs. In contrast, BAPTA-AM attenuated the effects of roscovitine on IPSCs. These results suggest that roscovitine augmented glutamate release by activating the release machinery located distally from the Cav 2.1 channel clusters, while it enhanced GABA release in a manner less dependent on those at distal sites. Therefore, the spatial relationships among Ca2+ channels, buffers, and sensors are critical determinants of the differential facilitatory actions of roscovitine on glutamatergic and GABAergic synapses in the cerebellar cortex.


Assuntos
Sinapses , Transmissão Sináptica , Animais , Cerebelo , Neurotransmissores , Terminações Pré-Sinápticas , Ratos , Roscovitina
18.
Nat Commun ; 12(1): 6021, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34654818

RESUMO

The mammalian brain relies on neurochemistry to fulfill its functions. Yet, the complexity of the brain metabolome and its changes during diseases or aging remain poorly understood. Here, we generate a metabolome atlas of the aging wildtype mouse brain from 10 anatomical regions spanning from adolescence to old age. We combine data from three assays and structurally annotate 1,547 metabolites. Almost all metabolites significantly differ between brain regions or age groups, but not by sex. A shift in sphingolipid patterns during aging related to myelin remodeling is accompanied by large changes in other metabolic pathways. Functionally related brain regions (brain stem, cerebrum and cerebellum) are also metabolically similar. In cerebrum, metabolic correlations markedly weaken between adolescence and adulthood, whereas at old age, cross-region correlation patterns reflect decreased brain segregation. We show that metabolic changes can be mapped to existing gene and protein brain atlases. The brain metabolome atlas is publicly available ( https://mouse.atlas.metabolomics.us/ ) and serves as a foundation dataset for future metabolomic studies.


Assuntos
Envelhecimento/metabolismo , Encéfalo/metabolismo , Metaboloma , Animais , Cerebelo/metabolismo , Feminino , Masculino , Redes e Vias Metabólicas , Metabolômica , Camundongos , Esfingolipídeos
19.
Int J Mol Sci ; 22(19)2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34639196

RESUMO

Human exposure to methylmercury (MeHg) is currently high in regions such as the Amazon. Understanding the molecular changes associated with MeHg-induced neurotoxicity and the crosstalk with the periphery is essential to support early diagnoses. This work aimed to evaluate cellular and molecular changes associated with behavioral alterations in MeHg acute exposure and the possible changes in extracellular vesicles (EVs) number and S100ß content. Adults male Wistar rats were orally treated with 5 mg/kg for four days. Behavioral performance, molecular and histological changes in the cerebellum, and plasma EVs were assessed. MeHg-intoxicated animals performed significantly worse in behavioral tests. MeHg increased the number of GFAP+ cells and GFAP and S100ß mRNA expression in the cerebellum but no change in NeuN+ or IBA-1+ cells number was detected. The number of exosomes isolated from plasma were decreased by the metal. S100B mRNA was detected in circulating plasma EVs cargo in MeHg exposure. Though preliminary, our results suggest astrocytic reactivity is displaying a protective role once there was no neuronal death. Interestingly, the reduction in exosomes number could be a new mechanism associated with MeHg-induced neurotoxicity and plasma EVs could represent a source of future biomarkers in MeHg intoxication.


Assuntos
Encéfalo/patologia , Cerebelo/patologia , Poluentes Ambientais/toxicidade , Vesículas Extracelulares/patologia , Compostos de Metilmercúrio/toxicidade , Síndromes Neurotóxicas/patologia , Animais , Encéfalo/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Vesículas Extracelulares/efeitos dos fármacos , Masculino , Síndromes Neurotóxicas/etiologia , Ratos , Ratos Wistar
20.
Artigo em Inglês | MEDLINE | ID: mdl-34639359

RESUMO

Cerebellar ataxias (CAs) manifest with a combination of motor incoordination, cognitive, affective and recently identified social symptoms. Novel therapies aim to stop the progression of the subgroup of the degenerative ataxias, or even to cure the disease with a functional and anatomical restoration of the cerebellar circuitry in the near future. The goal of stopping the progression of the disease is particularly relevant if applied at a very early stage of the disease, when the cerebellar reserve is only slightly impaired. Therefore, the search of the prodromal phase or pre-ataxic stage of CAs represents a very important challenge for the scientific community. The identification of pre-manifest individuals and the recruitment of individuals at risk has become a key-challenge to address neuroprotective therapies. The feasibility is high due to the recent progress in the biological and morphological biomarkers of CAs.


Assuntos
Ataxia Cerebelar , Doenças Cerebelares , Doenças Cerebelares/diagnóstico , Cerebelo , Humanos , Sintomas Prodrômicos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...