Publicação
The role of astrocytic metabotropic glutamate receptor 5 in cognitive function
| Resumo: | Over the years, increasing evidence has been demonstrating the key role of astrocytes in the brain, namely in modulations of synapses, neuronal networks and behavior, proving that these are more than mere supportive cells. Indeed, astrocytes gained recognition as the third active element of a synapse. In this tripartite synapse concept, while interacting closely with neurons, these cells can modulate neuronal activity by sensing, processing, integrating and responding to synaptic transmission. Astrocytes were firstly shown to sense glutamate, the most abundant excitatory neurotransmitter in the brain, which occurs mostly by activation of metabotropic glutamate receptor 5 (mGluR5). Activation of mGluR5 triggers Ca2+ elevations in astrocytes with consequences for synaptic function in cortico-limbic areas that are critical for cognitive processing. However, the majority of these studies were focused on the biological role of mGluR5 in young rodents, often using in vitro or ex vivo approaches. Thus, further studies are needed to better understand the impact of astrocytic mGluR5 in cognitive processing of adult mice. In this dissertation, we have generated two mouse models with temporally controlled deletion of mGluR5 in astrocytes, taking advantage of a mouse line carrying the mGluR5 flanked by loxP sites. Firstly, by inducing genetic recombination through a tamoxifen-inducible Cre--loxP system in astrocytes from the whole brain (GLAST-mGluR5KO mouse) and secondly by inducing ablation of the gene specifically in astrocytes from the hippocampus, following an injection of a rAAV5-GFAP-mCherry-Cre virus (dHIP-GFAPmGluR5KO mouse). A detailed behavior characterization of these mouse models showed that GLASTmGluR5KO and dHIP-GFAP-mGluR5KO mice do not present any anxious- or depressive -like phenotype or abnormal locomotor activity. Furthermore, cognitive assessment of these mice showed that GLASTmGluR5KO mice display normal spatial reference memory but enhanced behavior flexibility in Morris Water Maze (MWM). However, in the Contextual Fear Conditioning (CFC) these mice presented impaired fear memory. The behavioral assessment of dHIP-GFAP-mGluR5KO mice also revealed normal spatial reference memory, but impaired behavior flexibility, as shown in the reversal learning task of the MWM. In addition to behavior characterization, molecular analysis of GLAST-mGluR5KO mice showed a decreased expression levels of GFAP gene upon mGluR5 deletion. Overall, by using these different approaches to modulate astrocytic mGluR5 in adulthood we observed region-specific cognitive phenotypes. These evidences confirm the involvement of astrocytic mGluR5 in cognition and opens future perspectives in the field that urge to be addressed. |
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| Autores principais: | Viana, João Filipe Oliveira |
| Assunto: | mGluR5 Prefrontal cortex Astrócito Cognição Córtex pré-frontal Hipocampo Astrocyte Cognition Hippocampus |
| Ano: | 2019 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | inglês |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | Over the years, increasing evidence has been demonstrating the key role of astrocytes in the brain, namely in modulations of synapses, neuronal networks and behavior, proving that these are more than mere supportive cells. Indeed, astrocytes gained recognition as the third active element of a synapse. In this tripartite synapse concept, while interacting closely with neurons, these cells can modulate neuronal activity by sensing, processing, integrating and responding to synaptic transmission. Astrocytes were firstly shown to sense glutamate, the most abundant excitatory neurotransmitter in the brain, which occurs mostly by activation of metabotropic glutamate receptor 5 (mGluR5). Activation of mGluR5 triggers Ca2+ elevations in astrocytes with consequences for synaptic function in cortico-limbic areas that are critical for cognitive processing. However, the majority of these studies were focused on the biological role of mGluR5 in young rodents, often using in vitro or ex vivo approaches. Thus, further studies are needed to better understand the impact of astrocytic mGluR5 in cognitive processing of adult mice. In this dissertation, we have generated two mouse models with temporally controlled deletion of mGluR5 in astrocytes, taking advantage of a mouse line carrying the mGluR5 flanked by loxP sites. Firstly, by inducing genetic recombination through a tamoxifen-inducible Cre--loxP system in astrocytes from the whole brain (GLAST-mGluR5KO mouse) and secondly by inducing ablation of the gene specifically in astrocytes from the hippocampus, following an injection of a rAAV5-GFAP-mCherry-Cre virus (dHIP-GFAPmGluR5KO mouse). A detailed behavior characterization of these mouse models showed that GLASTmGluR5KO and dHIP-GFAP-mGluR5KO mice do not present any anxious- or depressive -like phenotype or abnormal locomotor activity. Furthermore, cognitive assessment of these mice showed that GLASTmGluR5KO mice display normal spatial reference memory but enhanced behavior flexibility in Morris Water Maze (MWM). However, in the Contextual Fear Conditioning (CFC) these mice presented impaired fear memory. The behavioral assessment of dHIP-GFAP-mGluR5KO mice also revealed normal spatial reference memory, but impaired behavior flexibility, as shown in the reversal learning task of the MWM. In addition to behavior characterization, molecular analysis of GLAST-mGluR5KO mice showed a decreased expression levels of GFAP gene upon mGluR5 deletion. Overall, by using these different approaches to modulate astrocytic mGluR5 in adulthood we observed region-specific cognitive phenotypes. These evidences confirm the involvement of astrocytic mGluR5 in cognition and opens future perspectives in the field that urge to be addressed. |
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