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The Role of microglia in synaptic pruning during multiple sclerosis
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A prevalência de défices cognitivos em doentes com esclerose múltipla (EM) é elevada. Mesmo assim, os mecanismos subjacentes ao seu aparecimento continuam por esclarecer. A microglia são as principais células imunitárias do sistema nervoso central e possuem várias funções. Para além de defender o parênquima cerebral, estas células também regulam a função neuronal, promovem a sobrevivência de neurónios e oligodendrócitos, contribuem para o desenvolvimento dos axónios e gerem a formação e eliminação de sinapses. Nos últimos anos, tem-se proposto que a microglia remove excessiva e inadequadamente as sinapses do hipocampo, resultando em alterações da conectividade e subsequentemente em défices cognitivos. Neste estudo, examinámos amostras humanas de hipocampo de pessoas saudáveis e comparámos com amostras de doentes com EM que apresentavam a função cognitiva preservada ou afetada de modo a avaliar possíveis alterações na densidade e a morfologia da microglia, e na capacidade de remoção de vesículas sinápticas (excitatórias e inibitórias) pela microglia. Embora não tenhamos observado diferenças significativas em termos de densidade microglial entre os diferentes grupos, pudemos distinguir algumas alterações morfológicas que sugerem a ativação e interação da microglia com o ambiente circundante, nomeadamente em doentes de EM com défices cognitivos. A análise da quantificação de vesiculas sinápticas fagocitadas pela microglia revelou um aumento do número de elementos pré-sinápticos excitatórios no interior da microglia de doentes com EM e disfunção cognitiva, em comparação com os grupos de doentes com EM e função cognitiva preservada e de controlos saudáveis. Estes resultados sugerem que a eliminação de sinapses glutamatérgicas mediada pela microglia poderá contribuir para alterações da função cognitiva em doentes com EM.
Cognitive impairment is highly prevalent in multiple sclerosis (MS). Yet, the mechanisms underlying cognitive impairment remain elusive. Microglia, the primary immune cells of the central nervous system, have numerous roles. Beyond their immune functions, they also regulate neuronal activity, support neuronal and oligodendrocyte survival, contribute to axonal tract development, and manage the formation and pruning of synapses. It has been proposed that, during neuroinflammation, microglia might inappropriately prune synapses within the hippocampus, leading to connectivity changes and subsequent cognitive deficits. Here, we examined human post-mortem hippocampal slices from healthy controls and compared them to samples from MS patients with preserved or affected cognition to evaluate potential changes in microglial density and morphology, and in microglia pruning of synaptic vesicles (both excitatory and inhibitory). Although we did not observe significant differences in terms of microglial cell density in the different groups, we did distinguish some morphological changes that suggest their activation and interaction with the surrounding environment, namely in the group of cognitively impaired MS patients. Our analysis of the synaptic puncta phagocyted by microglia unveiled an increased count of presynaptic excitatory elements within microglia in samples from cognitively impaired MS patients when compared to those with preserved cognitive function and the healthy control group. These findings suggest that microglial elimination of glutamatergic synapses may contribute to cognitive function changes in individuals with MS.
Cognitive impairment is highly prevalent in multiple sclerosis (MS). Yet, the mechanisms underlying cognitive impairment remain elusive. Microglia, the primary immune cells of the central nervous system, have numerous roles. Beyond their immune functions, they also regulate neuronal activity, support neuronal and oligodendrocyte survival, contribute to axonal tract development, and manage the formation and pruning of synapses. It has been proposed that, during neuroinflammation, microglia might inappropriately prune synapses within the hippocampus, leading to connectivity changes and subsequent cognitive deficits. Here, we examined human post-mortem hippocampal slices from healthy controls and compared them to samples from MS patients with preserved or affected cognition to evaluate potential changes in microglial density and morphology, and in microglia pruning of synaptic vesicles (both excitatory and inhibitory). Although we did not observe significant differences in terms of microglial cell density in the different groups, we did distinguish some morphological changes that suggest their activation and interaction with the surrounding environment, namely in the group of cognitively impaired MS patients. Our analysis of the synaptic puncta phagocyted by microglia unveiled an increased count of presynaptic excitatory elements within microglia in samples from cognitively impaired MS patients when compared to those with preserved cognitive function and the healthy control group. These findings suggest that microglial elimination of glutamatergic synapses may contribute to cognitive function changes in individuals with MS.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2023, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Multiple sclerosis Cognitive impairment Microglia Synaptic pruning Neuroinflammation Mestrado Integrado - 2023