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1.
Proc Natl Acad Sci U S A ; 118(47)2021 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-34782467

RESUMO

Nondegradative ubiquitin chains attached to specific targets via Lysine 63 (K63) residues have emerged to play a fundamental role in synaptic function. The K63-specific deubiquitinase CYLD has been widely studied in immune cells and lately also in neurons. To better understand if CYLD plays a role in brain and synapse homeostasis, we analyzed the behavioral profile of CYLD-deficient mice. We found that the loss of CYLD results in major autism-like phenotypes including impaired social communication, increased repetitive behavior, and cognitive dysfunction. Furthermore, the absence of CYLD leads to a reduction in hippocampal network excitability, long-term potentiation, and pyramidal neuron spine numbers. By providing evidence that CYLD can modulate mechanistic target of rapamycin (mTOR) signaling and autophagy at the synapse, we propose that synaptic K63-linked ubiquitination processes could be fundamental in understanding the pathomechanisms underlying autism spectrum disorder.


Assuntos
Autofagia/fisiologia , Hipocampo/metabolismo , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Transtorno do Espectro Autista , Transtorno Autístico , Enzima Desubiquitinante CYLD , Feminino , Lisina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos , Proteínas do Tecido Nervoso , Neurônios/metabolismo , Sinapses/metabolismo , Ubiquitina/metabolismo , Ubiquitinação
2.
Sci Rep ; 11(1): 6649, 2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33758244

RESUMO

Aberrant activity of local functional networks underlies memory and cognition deficits in Alzheimer's disease (AD). Hyperactivity was observed in microcircuits of mice AD-models showing plaques, and also recently in early stage AD mutants prior to amyloid deposition. However, early functional effects of AD on cortical microcircuits remain unresolved. Using two-photon calcium imaging, we found altered temporal distributions (burstiness) in the spontaneous activity of layer II/III visual cortex neurons, in a mouse model of familial Alzheimer's disease (5xFAD), before plaque formation. Graph theory (GT) measures revealed a distinct network topology of 5xFAD microcircuits, as compared to healthy controls, suggesting degradation of parameters related to network robustness. After treatment with acitretin, we observed a re-balancing of those network measures in 5xFAD mice; particularly in the mean degree distribution, related to network development and resilience, and post-treatment values resembled those of age-matched controls. Further, behavioral deficits, and the increase of excitatory synapse numbers in layer II/III were reversed after treatment. GT is widely applied for whole-brain network analysis in human neuroimaging, we here demonstrate the translational value of GT as a multi-level tool, to probe networks at different levels in order to assess treatments, explore mechanisms, and contribute to early diagnosis.


Assuntos
Acitretina/farmacologia , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Vias Neurais/efeitos dos fármacos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Ondas Encefálicas , Cálcio/metabolismo , Modelos Animais de Doenças , Humanos , Imuno-Histoquímica , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Imagem Óptica , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Agregação Patológica de Proteínas , Sinapses/efeitos dos fármacos , Sinapses/metabolismo
3.
Cell Rep ; 28(1): 11-20.e9, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31269433

RESUMO

Myosin VI is an actin-based cytoskeletal motor implicated in various steps of membrane trafficking. Here, we investigated whether this myosin is crucial for synaptic function and plasticity in neurons. We find that myosin VI localizes at cerebellar parallel fiber to Purkinje cell synapses and that the myosin is indispensable for long-term depression of AMPA-receptor-mediated synaptic signal transmission at this synapse. Moreover, direct visualization of GluA2-containing AMPA receptors in Purkinje cells reveals that the myosin drives removal of AMPA receptors from the surface of dendritic spines in an activity-dependent manner. Co-immunoprecipitation and super-resolution microscopy indicate that specifically the interaction of myosin VI with the clathrin adaptor component α-adaptin is important during long-term depression. Together, these data suggest that myosin VI directly promotes clathrin-mediated endocytosis of AMPA receptors in Purkinje cells to mediate cerebellar long-term depression. Our results provide insights into myosin VI function and the molecular mechanisms underlying synaptic plasticity.


Assuntos
Cerebelo/metabolismo , Depressão Sináptica de Longo Prazo , Cadeias Pesadas de Miosina/metabolismo , Neurônios/metabolismo , Receptores de AMPA/metabolismo , Subunidades alfa do Complexo de Proteínas Adaptadoras/metabolismo , Animais , Células Cultivadas , Cerebelo/citologia , Cerebelo/fisiologia , Clatrina/metabolismo , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/metabolismo , Endocitose/genética , Endocitose/fisiologia , Hipocampo/citologia , Hipocampo/metabolismo , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Cadeias Pesadas de Miosina/antagonistas & inibidores , Cadeias Pesadas de Miosina/genética , Células de Purkinje/metabolismo , Receptores de AMPA/agonistas , Receptores de AMPA/química , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologia
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