RESUMO
The triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial innate immune receptor associated with a lethal form of early, progressive dementia, Nasu-Hakola disease, and with an increased risk of Alzheimer's disease. Microglial defects in phagocytosis of toxic aggregates or apoptotic membranes were proposed to be at the origin of the pathological processes in the presence of Trem2 inactivating mutations. Here, we show that TREM2 is essential for microglia-mediated synaptic refinement during the early stages of brain development. The absence of Trem2 resulted in impaired synapse elimination, accompanied by enhanced excitatory neurotransmission and reduced long-range functional connectivity. Trem2-/- mice displayed repetitive behavior and altered sociability. TREM2 protein levels were also negatively correlated with the severity of symptoms in humans affected by autism. These data unveil the role of TREM2 in neuronal circuit sculpting and provide the evidence for the receptor's involvement in neurodevelopmental diseases.
Assuntos
Encéfalo/imunologia , Glicoproteínas de Membrana/imunologia , Microglia/imunologia , Neurônios/imunologia , Receptores Imunológicos/imunologia , Sinapses/imunologia , Animais , Transtorno Autístico/genética , Transtorno Autístico/imunologia , Transtorno Autístico/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Células Cultivadas , Humanos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/citologia , Microglia/metabolismo , Neurônios/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Sinapses/metabolismo , Transmissão Sináptica/genética , Transmissão Sináptica/imunologiaRESUMO
Neuronal circuit assembly requires the fine balance between synapse formation and elimination. Microglia, through the elimination of supernumerary synapses, have an established role in this process. While the microglial receptor TREM2 and the soluble complement proteins C1q and C3 are recognized as key players, the neuronal molecular components that specify synapses to be eliminated are still undefined. Here, we show that exposed phosphatidylserine (PS) represents a neuronal "eat-me" signal involved in microglial-mediated pruning. In hippocampal neuron and microglia co-cultures, synapse elimination can be partially prevented by blocking accessibility of exposed PS using Annexin V or through microglial loss of TREM2. In vivo, PS exposure at both hippocampal and retinogeniculate synapses and engulfment of PS-labeled material by microglia occurs during established developmental periods of microglial-mediated synapse elimination. Mice deficient in C1q, which fail to properly refine retinogeniculate connections, have elevated presynaptic PS exposure and reduced PS engulfment by microglia. These data provide mechanistic insight into microglial-mediated synapse pruning and identify a novel role of developmentally regulated neuronal PS exposure that is common among developing brain structures.
Assuntos
Hipocampo/metabolismo , Microglia/metabolismo , Neurônios/metabolismo , Fosfatidilserinas/metabolismo , Sinapses/metabolismo , Animais , Técnicas de Cocultura , Complemento C1q/genética , Complemento C1q/metabolismo , Complemento C3/genética , Complemento C3/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Fosfatidilserinas/genética , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Sinapses/genéticaRESUMO
Prion protein (PrP) mutations are linked to genetic prion diseases, a class of phenotypically heterogeneous neurodegenerative disorders with invariably fatal outcome. How mutant PrP triggers neurodegeneration is not known. Synaptic dysfunction precedes neuronal loss but it is not clear whether, and through which mechanisms, disruption of synaptic activity ultimately leads to neuronal death. Here we show that mutant PrP impairs the secretory trafficking of AMPA receptors (AMPARs). Specifically, intracellular retention of the GluA2 subunit results in synaptic exposure of GluA2-lacking, calcium-permeable AMPARs, leading to increased calcium permeability and enhanced sensitivity to excitotoxic cell death. Mutant PrPs linked to different genetic prion diseases affect AMPAR trafficking and function in different ways. Our findings identify AMPARs as pathogenic targets in genetic prion diseases, and support the involvement of excitotoxicity in neurodegeneration. They also suggest a mechanistic explanation for how different mutant PrPs may cause distinct disease phenotypes.
Assuntos
Cálcio/metabolismo , Neurônios/metabolismo , Proteínas PrPSc/metabolismo , Receptores de AMPA/metabolismo , Sinapses/metabolismo , Animais , Morte Celular/fisiologia , Camundongos , Permeabilidade , Transporte Proteico/fisiologiaRESUMO
[This corrects the article DOI: 10.1371/journal.ppat.1008654.].
RESUMO
Although behavioural defensive responses have been recorded several times in both laboratory and natural habitats, their neural mechanisms have seldom been investigated. To explore how chemical, water-borne cues are conveyed to the forebrain and instruct behavioural responses in anuran larvae, we conditioned newly hatched agile frog tadpoles using predator olfactory cues, specifically either native odonate larvae or alien crayfish kairomones. We expected chronic treatments to influence the basal neuronal activity of the tadpoles' mitral cells and alter their sensory neuronal connections, thereby impacting information processing. Subsequently, these neurons were acutely perfused, and their responses were compared with the defensive behaviour of tadpoles previously conditioned and exposed to the same cues. Tadpoles conditioned with odonate cues differed in both passive and active cell properties compared to those exposed to water (controls) or crayfish cues. The observed upregulation of membrane conductance and increase in both the number of active synapses and receptor density at the postsynaptic site are believed to have enhanced their responsiveness to external stimuli. Odonate cues also affected the resting membrane potential and firing rate of mitral cells during electrophysiological patch-clamp recordings, suggesting a rearrangement of the repertoire of voltage-dependent conductances expressed in cell membranes. These recorded neural changes may modulate the induction of an action potential and transmission of information. Furthermore, the recording of neural activity indicated that the lack of defensive responses towards non-native predators is due to the non-recognition of their olfactory cues.
Assuntos
Sinais (Psicologia) , Larva , Comportamento Predatório , Animais , Larva/fisiologia , Comportamento Predatório/fisiologia , Anuros/fisiologia , Neurônios Receptores Olfatórios/fisiologia , Astacoidea/fisiologiaRESUMO
The role of microglia in controlling synapse homeostasis is becoming increasingly recognized by the scientific community. In particular, the microglia-mediated elimination of supernumerary synapses during development lays the basis for the correct formation of neuronal circuits in adulthood, while the possible reactivation of this process in pathological conditions, such as schizophrenia or Alzheimer's Disease, provides a promising target for future therapeutic strategies. The methodological approaches to investigate microglial synaptic engulfment include different in vitro and in vivo settings. Basic in vitro assays, employing isolated microglia and microbeads, apoptotic membranes, liposomes or synaptosomes allow the quantification of the microglia phagocytic abilities, while co-cultures of microglia and neurons, deriving from either WT or genetically modified mice models, provide a relatively manageable setting to investigate the involvement of specific molecular pathways. Further detailed analysis in mice brain is then mandatory to validate the in vitro assays as representative for the in vivo situation. The present review aims to dissect the main technical approaches to investigate microglia-mediated phagocytosis of neuronal and synaptic substrates in critical developmental time windows.
Assuntos
Microglia , Plasticidade Neuronal , Neurociências/métodos , Sinapses , Animais , Humanos , Neurogênese/fisiologia , Fagocitose/fisiologiaRESUMO
Hericium erinaceus is an edible and medicinal mushroom with potential neuroprotective effects. The study of H. erinaceus has attracted considerable attention during the past 10 years, particularly with regard to its potential utility in the treatment of motor dysfunction, Alzheimer disease, and other forms of dementia. We previously determined that oral supplementation with H. erinaceus results in significant improvements in novelty-seeking behavior and novel object recognition in mice. In this study, H. erinaceus was added to the diets of wild-type mice for 2 months, and effects on spatial memory were evaluated by means of a Y maze and an object location task. We found that H. erinaceus increased general locomotor activity but had no effect on spatial memory. Thus, oral supplementation with H. erinaceus yields specific and selective improvements in recognition memory without altering spatial working memory, which supports the hypothesis that recognition memory can be modeled as a dual process. In this model, the perirhinal cortex supports the recognition of individual items as part of a circuit involved in familiarity with an encountered stimulus, whereas the hippocampus supports recollected associations and relationships between stimuli.
Assuntos
Agaricales/química , Suplementos Nutricionais , Fármacos Neuroprotetores/administração & dosagem , Memória Espacial/efeitos dos fármacos , Administração Oral , Doença de Alzheimer/tratamento farmacológico , Animais , Carpóforos/química , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Reconhecimento Psicológico/efeitos dos fármacosRESUMO
Actin-based remodeling underlines spine morphogenesis and plasticity and is crucially involved in the processes that constantly reshape the circuitry of the adult brain in response to external stimuli, leading to learning and memory formation and supporting cognitive functions. Hence spine morphology and synaptic strength are tightly linked and indeed abnormalities in spine number and morphology have been described in a number of neurological disorders such as autism spectrum disorders (ASDs), schizophrenia and intellectual disabilities. We have recently demonstrated that the actin regulating protein, Epidermal growth factor receptor pathway substrate 8 (Eps8), is essential for spine growth and long term potentiation. Indeed, mice lacking Eps8 display immature filopodia-like spines, which are unable to undergo potentiation, and are impaired in cognitive functions. Furthermore, reduced levels of Eps8 have been found in the brain of a cohort of patients affected by ASD compared to controls. Here we investigated whether the lack of Eps8, which is also part of the N-methyl-d-aspartate (NMDA) receptor complex, affects the functional maturation of the postsynaptic compartment. Our results demonstrate that Eps8 knock out mice (Eps8 KO) neurons display altered synaptic expression and subunit composition of NMDA receptors (i.e., increased GluN2B-, decreased GluN2A-containing receptors) and impaired GluN2B to GluN2A subunit shift. Indeed Eps8 KO neurons display increased content of GluN2B containing NMDA receptors both at the synaptic and extrasynaptic level. Furthermore, Eps8 KO neurons display an increased content of extra-synaptic GluN2B-containing receptors, suggesting that also the synaptic targeting of NMDA receptors is affected by the lack of Eps8. These data demonstrate that, besides regulation of spine morphogenesis, Eps8 also regulates the synaptic balance of NMDA receptors subunits GluN2A and GluN2B.