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1.
Mol Neurobiol ; 54(3): 1759-1776, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-26884267

RESUMO

The postsynaptic density (PSD) consists of a lattice-like array of interacting proteins that organizes and stabilizes synaptic receptors, ion channels, structural proteins, and signaling molecules required for normal synaptic transmission and synaptic function. The scaffolding and hub protein postsynaptic density protein-95 (PSD-95) is a major element of central chemical synapses and interacts with glutamate receptors, cell adhesion molecules, and cytoskeletal elements. In fact, PSD-95 can regulate basal synaptic stability as well as the activity-dependent structural plasticity of the PSD and, therefore, of the excitatory chemical synapse. Several studies have shown that PSD-95 is highly enriched at excitatory synapses and have identified multiple protein structural domains and protein-protein interactions that mediate PSD-95 function and trafficking to the postsynaptic region. PSD-95 is also a target of several signaling pathways that induce posttranslational modifications, including palmitoylation, phosphorylation, ubiquitination, nitrosylation, and neddylation; these modifications determine the synaptic stability and function of PSD-95 and thus regulate the fates of individual dendritic spines in the nervous system. In the present work, we review the posttranslational modifications that regulate the synaptic localization of PSD-95 and describe their functional consequences. We also explore the signaling pathways that induce such changes.


Assuntos
Proteína 4 Homóloga a Disks-Large/análise , Proteína 4 Homóloga a Disks-Large/metabolismo , Densidade Pós-Sináptica/química , Densidade Pós-Sináptica/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Animais , Proteína 4 Homóloga a Disks-Large/genética , Humanos , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismo , Plasticidade Neuronal/fisiologia , Densidade Pós-Sináptica/genética , Sinapses/química , Sinapses/genética , Sinapses/metabolismo
2.
Thyroid ; 22(9): 951-63, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22870949

RESUMO

BACKGROUND: Adult hypothyroidism is a highly prevalent condition that impairs processes, such as learning and memory. Even though tetra-iodothyronine (T(4)) treatment can overcome the hypothyroidism in the majority of cases, it cannot fully recover the patient's learning capacity and memory. In this work, we analyzed the cellular and molecular changes in the adult brain occurring with the development of experimental hypothyroidism. METHODS: Adult male Sprague-Dawley rats were treated with 6-propyl-2-thiouracil (PTU) for 20 days to induce hypothyroidism. Neuronal and astrocyte apoptosis were analyzed in the hippocampus of control and hypothyroid adult rats by confocal microscopy. The content of brain-derived neurotrophic factor (BDNF) was analyzed using enzyme-linked immunosorbent assay (ELISA) and in situ hybridization. The glutamatergic synapse and the postsynaptic density (PSD) were analyzed by electron microscopy. The content of PSD proteins like tyrosine receptor kinase B (TrkB), p75, and N-methyl-D-aspartate receptor (NMDAr) were analyzed by immunoblot. RESULTS: We observed that the hippocampus of hypothyroid adult rats displayed increased apoptosis levels in neurons and astrocyte and reactive gliosis compared with controls. Moreover, we found that the amount of BDNF mRNA was higher in the hippocampus of hypothyroid rats and the content of TrkB, the receptor for BDNF, was reduced at the PSD of the CA3 region of hypothyroid rats, compared with controls. We also observed that the glutamatergic synapses from the stratum radiatum of CA3 from hypothyroid rats, contained thinner PSDs than control rats. This observation was in agreement with a reduced content of NMDAr subunits at the PSD in hypothyroid animals. CONCLUSIONS: Our data suggest that adult hypothyroidism affects the hippocampus by a mechanism that alters the composition of PSD, reduces neuronal and astrocyte survival, and alters the content of the signaling neurotrophic factors, such as BDNF.


Assuntos
Astrócitos/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Gliose/patologia , Hipotireoidismo/complicações , Neurônios/patologia , Densidade Pós-Sináptica/patologia , Animais , Antitireóideos/efeitos adversos , Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/análise , Gliose/induzido quimicamente , Hipocampo/química , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/ultraestrutura , Hipotireoidismo/induzido quimicamente , Masculino , Neurônios/efeitos dos fármacos , Densidade Pós-Sináptica/química , Densidade Pós-Sináptica/efeitos dos fármacos , Propiltiouracila/efeitos adversos , Ratos , Ratos Sprague-Dawley , Receptor trkB/análise , Receptores de N-Metil-D-Aspartato/análise
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