RESUMO
Idiopathic intracranial hypertension (IIH) primarily affects fertile, overweight women, and presents with the symptoms of raised intracranial pressure. The etiology is unknown but has been thought to relate to cerebrospinal fluid disturbance or cerebral venous stenosis. We have previously found evidence that IIH is also a disease of the brain parenchyma, evidenced by alterations at the neurogliovascular interface, including astrogliosis, pathological changes in the basement membrane and pericytes, and alterations of perivascular aquaporin-4. The aim of this present electron microscopic study was to examine whether mitochondria phenotype was changed in IIH, particularly focusing on perivascular astrocytic endfeet and neurons (soma and pre- and postsynaptic terminals). Cortical brain biopsies of nine reference individuals and eight IIH patients were analyzed for subcellular distribution and phenotypical features of mitochondria using transmission electron microscopy. We found significantly increased prevalence of pathological mitochondria and reduced number of normal mitochondria in astrocytic endfeet of IIH patients. The degree of astrogliosis correlated negatively with the number of normal mitochondria in astrocytic endfoot processes. Moreover, we found significantly increased number of pathological mitochondria in pre- and postsynaptic neuronal terminals, as well as significantly shortened distance between mitochondria and endoplasmic reticulum contacts. Finally, the length of postsynaptic density, a marker of synaptic strength, was on average reduced in IIH. The present data provide evidence of pathological mitochondria in perivascular astrocytes endfeet and neurons of IIH patients, highlighting that impaired metabolism at the neurogliovascular interface may be a facet of IIH.
Assuntos
Astrócitos/ultraestrutura , Córtex Cerebral/patologia , Mitocôndrias/patologia , Neurônios/ultraestrutura , Pseudotumor Cerebral/patologia , Adulto , Biópsia , Retículo Endoplasmático/ultraestrutura , Feminino , Gliose/etiologia , Gliose/patologia , Sistema Glinfático/ultraestrutura , Humanos , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Terminações Nervosas/ultraestrutura , Densidade Pós-Sináptica/ultraestrutura , Estudos Prospectivos , Pseudotumor Cerebral/complicações , Método Simples-Cego , Adulto JovemRESUMO
Age- and menopause-related deficits in working memory can be partially restored with estradiol replacement in women and female nonhuman primates. Working memory is a cognitive function reliant on persistent firing of dorsolateral prefrontal cortex (dlPFC) neurons that requires the activation of GluN2B-containing glutamate NMDA receptors. We tested the hypothesis that the distribution of phospho-Tyr1472-GluN2B (pGluN2B), a predominant form of GluN2B seen at the synapse, is sensitive to aging or estradiol treatment and coupled to working memory performance. First, ovariectomized young and aged rhesus monkeys (Macaca mulatta) received long-term cyclic vehicle (V) or estradiol (E) treatment and were tested on the delayed response (DR) test of working memory. Then, serial section electron microscopic immunocytochemistry was performed to quantitatively assess the subcellular distribution of pGluN2B. While the densities of pGluN2B immunogold particles in dlPFC dendritic spines were not different across age or treatment groups, the percentage of gold particles located within the synaptic compartment was significantly lower in aged-E monkeys compared to young-E and aged-V monkeys. On the other hand, the percentage of pGluN2B gold particles in the spine cytoplasm was decreased with E treatment in young, but increased with E in aged monkeys. In aged monkeys, DR average accuracy inversely correlated with the percentage of synaptic pGluN2B, while it positively correlated with the percentage of cytoplasmic pGluN2B. Together, E replacement may promote cognitive health in aged monkeys, in part, by decreasing the relative representation of synaptic pGluN2B and potentially protecting the dlPFC from calcium toxicity.
Assuntos
Envelhecimento , Estrogênios/administração & dosagem , Memória de Curto Prazo/fisiologia , Córtex Pré-Frontal/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Sinapses/fisiologia , Animais , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/fisiologia , Espinhas Dendríticas/ultraestrutura , Feminino , Macaca mulatta , Memória de Curto Prazo/efeitos dos fármacos , Fosforilação , Densidade Pós-Sináptica/ultraestrutura , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/ultraestrutura , Receptores de N-Metil-D-Aspartato/ultraestrutura , Sinapses/efeitos dos fármacos , Sinapses/ultraestruturaRESUMO
Tamoxifen (TAM) is a selective estrogen receptor modulator, widely used in the treatment and prevention of estrogen-dependent breast cancer. Although with great clinical results, women on TAM therapy still report several side effects, such as sexual dysfunction, which impairs quality of life. The anatomo-functional substrates of the human sexual behavior are still unknown; however, these same substrates are very well characterized in the rodent female sexual behavior, which has advantage of being a very simple reflexive response, dependent on the activation of estrogen receptors (ERs) in the ventrolateral division of the hypothalamic ventromedial nucleus (VMNvl). In fact, in the female rodent, the sexual behavior is triggered by increasing circulation levels of estradiol that changes the nucleus neurochemistry and modulates its intricate neuronal network. Therefore, we considered of notice the examination of the possible neurochemical alterations and the synaptic plasticity impairment in VMNvl neurons of estradiol-primed female rats treated with TAM that may be in the basis of this neurological disorder. Accordingly, we used stereological and biochemical methods to study the action of TAM in axospinous and axodendritic synaptic plasticity and on ER expression. The administration of TAM changed the VMNvl neurochemistry by reducing ERα mRNA and increasing ERß mRNA expression. Furthermore, present results show that TAM induced neuronal atrophy and reduced synaptic connectivity, favoring electrical inactivity. These data suggest that these cellular and molecular changes may be a possible neuronal mechanism of TAM action in the disruption of the VMNvl network, leading to the development of behavioral disorders.
Assuntos
Antineoplásicos Hormonais/administração & dosagem , Neurônios/efeitos dos fármacos , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Comportamento Sexual Animal/efeitos dos fármacos , Disfunções Sexuais Fisiológicas/induzido quimicamente , Tamoxifeno/administração & dosagem , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacos , Animais , Contagem de Células , Espinhas Dendríticas/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Feminino , Neurônios/metabolismo , Neurônios/ultraestrutura , Densidade Pós-Sináptica/efeitos dos fármacos , Densidade Pós-Sináptica/ultraestrutura , RNA Mensageiro/metabolismo , Ratos Wistar , Núcleo Hipotalâmico Ventromedial/metabolismo , Núcleo Hipotalâmico Ventromedial/ultraestruturaRESUMO
In Parkinson's disease, striatal dopamine depletion leads to plastic changes at excitatory corticostriatal and thalamostriatal synapses. The functional consequences of these responses on the expression of behavioral deficits are incompletely understood. In addition, most of the information on striatal synaptic plasticity has been obtained in models with severe striatal dopamine depletion, and less is known regarding changes during early stages of striatal denervation. Using a partial model of nigral cell loss based on intranigral injection of the proteasome inhibitor lactacystin, we demonstrate ultrastructural changes at corticostriatal synapses with a 15% increase in the length and 30% increase in the area of the postsynaptic densities at corticostriatal synapses 1 week following toxin administration. This increase was positively correlated with the performance of lactacystin-lesioned mice on the rotarod task, such that mice with a greater increase in the size of the postsynaptic density performed better on the rotarod task. We therefore propose that lengthening of the postsynaptic density at corticostriatal synapses acts as a compensatory mechanism to maintain motor function under conditions of partial dopamine depletion. The ultrastructure of thalamostriatal synapses remained unchanged following lactacystin administration. Our findings provide novel insights into the mechanisms of synaptic plasticity and behavioral compensation following partial loss of substantia nigra pars compacta neurons, such as those occurring during the early stages of Parkinson's disease.
Assuntos
Córtex Cerebral/fisiopatologia , Corpo Estriado/fisiopatologia , Plasticidade Neuronal , Doença de Parkinson/fisiopatologia , Sinapses/fisiologia , Acetilcisteína/administração & dosagem , Acetilcisteína/análogos & derivados , Animais , Comportamento Animal , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/ultraestrutura , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/ultraestrutura , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiopatologia , Vias Neurais/ultraestrutura , Plasticidade Neuronal/efeitos dos fármacos , Doença de Parkinson/patologia , Transtornos Parkinsonianos/induzido quimicamente , Parte Compacta da Substância Negra/efeitos dos fármacos , Densidade Pós-Sináptica/efeitos dos fármacos , Densidade Pós-Sináptica/ultraestrutura , Teste de Desempenho do Rota-Rod , Sinapses/efeitos dos fármacos , Sinapses/ultraestruturaRESUMO
Ankyrin repeat and sterile alpha motif domain-containing protein 1B (ANKS1B, also known as AIDA-1) is a major component of the postsynaptic density (PSD) in excitatory neurons where it concentrates at the electron-dense core under basal conditions and moves out during activity. This study investigates the molecular mechanism underlying activity-induced displacement of AIDA-1. Experiments with PSD fractions from brain indicate phosphorylation of AIDA-1 upon activation of endogenous CaMKII. Immuno-electron microscopy studies show that treatment of hippocampal neurons with NMDA results in an ~ 30 nm shift in the median distance of the AIDA-1 label from the postsynaptic membrane, an effect that is blocked by the CaMKII inhibitor tatCN21. CaMKII-mediated redistribution of AIDA-1 is similar to that observed for SynGAP. CaMKII-mediated removal of two abundant PSD-95-binding proteins from the PSD core during activity is expected to initiate a molecular reorganization at the PSD.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteínas de Transporte/metabolismo , Neurônios/metabolismo , Densidade Pós-Sináptica/metabolismo , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteínas de Transporte/genética , Hipocampo/metabolismo , Hipocampo/ultraestrutura , Humanos , Microscopia Imunoeletrônica , Neurônios/ultraestrutura , Peptídeos/farmacologia , Fosforilação , Densidade Pós-Sináptica/ultraestrutura , RatosRESUMO
Elderly females, particularly those carrying the apolipoprotein E (ApoE)-ε4 allele, have a higher risk of developing Alzheimer's disease (AD). However, the underlying mechanism for this increased susceptibility remains unclear. In this study, we investigated the effects of the ApoE genotype and gender on the proteome of synaptosomes. We isolated synaptosomes and used label-free quantitative proteomics, to report, for the first time, that the synaptosomal proteomic profiles in the cortex of female human-ApoE4 mice exhibited significantly reduced expression of proteins related to energy metabolism, which was accompanied by increased levels of oxidative stress. In addition, we also first demonstrated that the proteomic response in synaptic termini was more susceptible than that in the soma to the adverse effects induced by genders and genotypes. This suggests that synaptic mitochondria might be 'older' than mitochondria in the soma of neurons; therefore, they might contain increased cumulative damage from oxidative stress. Furthermore, female human-ApoE4 mice had much lower oestrogen levels in the cortex and treatment with oestrogen protected ApoE3 stable transfected C6 neurons from oxidative stress. Overall, this study reveals complex ApoE- and gender-dependent effects on synaptic function and also provides a basis for future studies of candidates based on specific pathways involved in the pathogenesis of AD. The lack of oestrogen-mediated protection regulated by the ApoE genotype led to synaptic mitochondrial dysfunction and increased oxidative stress, which might make older females more susceptible to AD.
Assuntos
Apolipoproteínas E/genética , Córtex Cerebral/ultraestrutura , Estresse Oxidativo/genética , Proteoma/metabolismo , Caracteres Sexuais , Sinaptossomos/metabolismo , Animais , Moléculas de Adesão Celular Neurônio-Glia/metabolismo , Estrogênios/farmacologia , Feminino , Glutationa/metabolismo , Dissulfeto de Glutationa/metabolismo , Humanos , Masculino , Malondialdeído/metabolismo , Espectrometria de Massas , Camundongos , Camundongos Transgênicos , Estresse Oxidativo/efeitos dos fármacos , Densidade Pós-Sináptica/metabolismo , Densidade Pós-Sináptica/ultraestrutura , Proteômica/métodos , Sinaptossomos/ultraestruturaRESUMO
C boutons are large, cholinergic, synaptic terminals that arise from local interneurons and specifically contact spinal α-motoneurons (MNs). C boutons characteristically display a postsynaptic specialization consisting of an endoplasmic reticulum-related subsurface cistern (SSC) of unknown function. In the present work, by using confocal microscopy and ultrastructural immunolabeling, we demonstrate that neuregulin-1 (NRG1) accumulates in the SSC of mouse spinal MNs. We also show that the NRG1 receptors erbB2 and erbB4 are presynaptically localized within C boutons, suggesting that NRG1-based retrograde signaling may occur in this type of synapse. In most of the cranial nuclei, MNs display the same pattern of NRG1 distribution as that observed in spinal cord MNs. Conversely, MNs in oculomotor nuclei, which are spared in amyotrophic lateral sclerosis (ALS), lack both C boutons and SSC-associated NRG1. NRG1 in spinal MNs is developmentally regulated and depends on the maintenance of nerve-muscle interactions, as we show after nerve transection experiments. Changes in NRG1 in C boutons were also investigated in mouse models of MN diseases: i.e., spinal muscular atrophy (SMNΔ7) and ALS (SOD1(G93A)). In both models, a transient increase in NRG1 in C boutons occurs during disease progression. These data increase our understanding of the role of C boutons in MN physiology and pathology.
Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Proteínas Aviárias/fisiologia , Neurônios Motores/metabolismo , Atrofia Muscular Espinal/metabolismo , Neuregulina-1/fisiologia , Organelas/química , Densidade Pós-Sináptica/química , Terminações Pré-Sinápticas/química , Esclerose Lateral Amiotrófica/patologia , Animais , Proteínas Aviárias/análise , Embrião de Galinha , Galinhas , Receptores ErbB/análise , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios Motores/patologia , Atrofia Muscular Espinal/patologia , Neuregulina-1/análise , Neuregulina-1/biossíntese , Neuregulina-1/genética , Densidade Pós-Sináptica/ultraestrutura , Terminações Pré-Sinápticas/ultraestrutura , Receptor ErbB-2/análise , Receptor ErbB-4 , Nervo Isquiático/lesões , Nervo Isquiático/ultraestrutura , Medula Espinal/citologia , Medula Espinal/embriologia , Medula Espinal/crescimento & desenvolvimentoRESUMO
The 53 kDa insulin receptor substrate protein (IRSp53) is highly enriched in the brain. Despite evidence that links mutations of IRSp53 with autism and other neuropsychiatric problems, the functional significance of this protein remains unclear. We used light and electron microscopic immunohistochemistry to demonstrate that IRSp53 is expressed throughout the adult rat brain. Labeling concentrated selectively in dendritic spines, where it was associated with the postsynaptic density (PSD). Surprisingly, its organization within the PSD of spiny excitatory neurons of neocortex and hippocampus differed from that within spiny inhibitory neurons of neostriatum and cerebellar cortex. The present data support previous suggestions that IRSp53 is involved in postsynaptic signaling, while hinting that its signaling role may differ in different types of neurons.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Encéfalo/metabolismo , Espinhas Dendríticas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Densidade Pós-Sináptica/metabolismo , Sinapses/metabolismo , Animais , Encéfalo/ultraestrutura , Espinhas Dendríticas/ultraestrutura , Imunofluorescência , Processamento de Imagem Assistida por Computador , Técnicas Imunoenzimáticas , Imuno-Histoquímica , Masculino , Microscopia Eletrônica , Neurônios/ultraestrutura , Densidade Pós-Sináptica/ultraestrutura , Ratos Sprague-Dawley , Sinapses/ultraestrutura , Ácido gama-Aminobutírico/metabolismoRESUMO
Postsynaptic membrane rafts are believed to play important roles in synaptic signaling, plasticity, and maintenance. We recently demonstrated the presence, at the electron microscopic level, of complexes consisting of membrane rafts and postsynaptic densities (PSDs) in detergent-resistant membranes (DRMs) prepared from synaptic plasma membranes (SPMs) ( Suzuki et al., 2011 , J Neurochem, 119, 64-77). To further explore these complexes, here we investigated the nature of the binding between purified SPM-DRMs and PSDs in vitro. In binding experiments, we used SPM-DRMs prepared after treating SPMs with n-octyl-ß-d-glucoside, because at concentrations of 1.0% or higher it completely separates SPM-DRMs and PSDs, providing substantially PSD-free unique SPM-DRMs as well as DRM-free PSDs. PSD binding to PSD-free DRMs was identified by mass spectrometry, Western blotting, and electron microscopy. PSD proteins were not incorporated into SPMs, and significantly less PSD proteins were incorporated into DRMs prepared from liver membranes, providing in vitro evidence that binding of PSDs to DRMs is specific and suggestion of the presence of specific interacting molecules. These specific interactions may have important roles in synaptic development, function, and plasticity in vivo. In addition, the binding system we developed may be a good tool to search for binding molecules and binding mechanisms between PSDs and rafts.
Assuntos
Microdomínios da Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Densidade Pós-Sináptica/metabolismo , Membranas Sinápticas/metabolismo , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Encéfalo/citologia , Encéfalo/ultraestrutura , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Colesterol/metabolismo , Gangliosídeo G(M1)/metabolismo , Masculino , Microdomínios da Membrana/ultraestrutura , Microscopia Eletrônica de Transmissão , Densidade Pós-Sináptica/ultraestrutura , Ratos , Ratos Wistar , Receptores de AMPA/metabolismo , Membranas Sinápticas/ultraestruturaRESUMO
Dendritic spines are important sites of excitatory neurotransmission in the brain with their function determined by their structure and molecular content. Alterations in spine number, morphology and receptor content are a hallmark of many psychiatric disorders, most notably those because of stress. We investigated the role of corticotropin-releasing factor (CRF) stress peptides on the plasticity of spines in the cerebellum, a structure implicated in a host of mental illnesses, particularly of a developmental origin. We used organotypic slice cultures of the cerebellum and restraint stress in behaving animals to determine whether CRF in vitro and stress in vivo affects Purkinje cell (PC) spine density. Application of CRF and urocortin (UCN) to cerebellar slice cultures increased the density of spines on PC signaling via CRF receptors (CRF-Rs) 1 and 2 and RhoA downregulation, although the structural phenotypes of the induced spines varied, suggesting that CRF-Rs differentially induce the outgrowth of functionally distinct populations of spines. Furthermore, CRF and UCN exert a trophic effect on the surface contact between synaptic elements by increasing active zones and postsynaptic densities and facilitating the alignment of pre- and post-synaptic membranes of synapses on PCs. In addition, 1 h of restraint stress significantly increased PC spine density compared with those animals that were only handled. This study provides unprecedented resolution of CRF pathways that regulate the structural machinery essential for synaptic transmission and provides a basis for understanding stress-induced mental illnesses.
Assuntos
Hormônio Liberador da Corticotropina/farmacologia , Espinhas Dendríticas/efeitos dos fármacos , Hormônios Peptídicos/farmacologia , Células de Purkinje/citologia , Estresse Psicológico/patologia , Sinapses/efeitos dos fármacos , Compostos de Anilina/farmacologia , Animais , Animais Recém-Nascidos , Cerebelo/citologia , Quelantes/farmacologia , Hormônio Liberador da Corticotropina/antagonistas & inibidores , Hormônio Liberador da Corticotropina/metabolismo , Espinhas Dendríticas/patologia , Espinhas Dendríticas/ultraestrutura , Ácido Egtázico/análogos & derivados , Ácido Egtázico/farmacologia , Corantes Fluorescentes/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Proteínas do Tecido Nervoso/metabolismo , Técnicas de Cultura de Órgãos , Técnicas de Patch-Clamp , Fragmentos de Peptídeos/farmacologia , Hormônios Peptídicos/metabolismo , Densidade Pós-Sináptica/efeitos dos fármacos , Densidade Pós-Sináptica/metabolismo , Densidade Pós-Sináptica/ultraestrutura , Células de Purkinje/patologia , Pirimidinas/farmacologia , Ratos , Bloqueadores dos Canais de Sódio/farmacologia , Estresse Psicológico/metabolismo , Sinapses/ultraestrutura , Tetrodotoxina/farmacologia , Fatores de Tempo , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismoRESUMO
R-type calcium channels (RTCCs) are well known for their role in synaptic plasticity, but little is known about their subcellular distribution across various neuronal compartments. Using subtype-specific antibodies, we characterized the regional and subcellular localization of Ca(v)2.3 in mice and rats at both light and electron microscopic levels. Ca(v)2.3 immunogold particles were found to be predominantly presynaptic in the interpeduncular nucleus, but postsynaptic in other brain regions. Serial section analysis of electron microscopic images from the hippocampal CA1 revealed a higher density of immunogold particles in the dendritic shaft plasma membrane compared with the pyramidal cell somata. However, the labeling densities were not significantly different among the apical, oblique, or basal dendrites. Immunogold particles were also observed over the plasma membrane of dendritic spines, including both synaptic and extrasynaptic sites. Individual spine heads contained <20 immunogold particles, with an average density of â¼260 immunoparticles per µm(3) spine head volume, in accordance with the density of RTCCs estimated using calcium imaging (Sabatini and Svoboda, 2000). The Ca(v)2.3 density was variable among similar-sized spine heads and did not correlate with the density in the parent dendrite, implying that spines are individual calcium compartments operating autonomously from their parent dendrites.
Assuntos
Canais de Cálcio Tipo R/metabolismo , Canais de Cálcio Tipo R/ultraestrutura , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte de Cátions/ultraestrutura , Neurônios/metabolismo , Neurônios/ultraestrutura , Análise de Variância , Animais , Animais Recém-Nascidos , Encéfalo/citologia , Canais de Cálcio Tipo R/química , Canais de Cálcio Tipo R/deficiência , Proteínas de Transporte de Cátions/química , Proteínas de Transporte de Cátions/deficiência , Membrana Celular/metabolismo , Membrana Celular/ultraestrutura , Dendritos/metabolismo , Dendritos/ultraestrutura , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/ultraestrutura , Epitopos/metabolismo , Feminino , Cobaias , Imageamento Tridimensional , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Imunoeletrônica , Peptídeos/metabolismo , Densidade Pós-Sináptica/metabolismo , Densidade Pós-Sináptica/ultraestrutura , Ratos , Estatística como Assunto , Estatísticas não Paramétricas , Frações Subcelulares/metabolismo , Frações Subcelulares/ultraestruturaRESUMO
The insulin receptor (IR) is a protein tyrosine kinase playing a pivotal role in the regulation of peripheral glucose metabolism and energy homoeostasis. IRs are also abundantly distributed in the cerebral cortex and hippocampus, where they regulate synaptic activity required for learning and memory. As the major anabolic hormone in mammals, insulin stimulates protein synthesis partially through the activation of the PI3K/Akt/mTOR pathway, playing fundamental roles in neuronal development, synaptic plasticity and memory. Here, by means of a multidisciplinary approach, we report that long-term synaptic plasticity and recognition memory are impaired in IR ß-subunit heterozygous mice. Since IR expression is diminished in type-2 diabetes as well as in Alzheimer's disease (AD) patients, these data may provide a mechanistic link between insulin resistance, impaired synaptic transmission and cognitive decline in humans with metabolic disorders.
Assuntos
Hipocampo/fisiopatologia , Deficiências da Aprendizagem/genética , Potenciação de Longa Duração/genética , Transtornos da Memória/genética , Proteínas do Tecido Nervoso/deficiência , Receptor de Insulina/deficiência , Reconhecimento Psicológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/psicologia , Feminino , Heterozigoto , Humanos , Resistência à Insulina , Deficiências da Aprendizagem/fisiopatologia , Transtornos da Memória/fisiopatologia , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Fosfatidilinositol 3-Quinases/fisiologia , Densidade Pós-Sináptica/ultraestrutura , Proteínas Proto-Oncogênicas c-akt/fisiologia , Receptor de Insulina/genética , Receptor de Insulina/fisiologia , Transdução de Sinais/fisiologia , Transmissão Sináptica/genética , Serina-Treonina Quinases TOR/fisiologiaRESUMO
Synaptic remodelling coordinated with dendritic growth is essential for proper development of neural connections. After establishment of synaptic contacts, synaptic junctions are thought to become stationary and provide fixed anchoring points for further dendritic growth. However, the possibility of active translocation of synapses along dendritic protrusions, to guide the proper arrangement of synaptic distribution, has not yet been fully investigated. Here we show that immature dendrites of γ-aminobutyric acid-positive interneurons form long protrusions and that these protrusions serve as conduits for retrograde translocation of synaptic contacts to the parental dendrites. This translocation process is dependent on microtubules and the activity of LIS1, an essential regulator of dynein-mediated motility. Suppression of this retrograde translocation results in disorganized synaptic patterns on interneuron dendrites. Taken together, these findings suggest the existence of an active microtubule-dependent mechanism for synaptic translocation that helps in the establishment of proper synaptic distribution on dendrites.