Publicação
The role of AP2γ transcription factor in the modulation of adult glutamatergic neurogenesis in depression
| Resumo: | Major depressive disorder (MDD) is a multidimensional psychiatric disease, considered by the World Health Organization as one of the leading causes of disability. Despite the importance of this disease in modern societies and the large investment of resources already made in its study, the processes underlying its pathophysiology remain poorly understood. Several hypotheses have been proposed to clarify the neurobiological mechanisms underlying this psychiatric disorder, being the link between adult hippocampal neurogenesis and MDD a central topic in the past decades. Previous studies have identified AP2γ as a key regulator of adult hippocampal neurogenesis in mice, being expressed in a subpopulation of adult transient amplifying progenitors, and acting as a regulator of basal progenitors, promoting proliferation and glutamatergic neuronal differentiation. Thus, we wanted to further explore the impact of AP2γ in brain neurophysiology and behavior during development and at adult stages, dissecting also its mechanisms both in healthy and depressive states. With this study, we were able to understand the impact of AP2γ in post-natal development and during juvenile age, through the AP2γ constitutive knockout (KO) model. In the developmental milestones assessment we did not find any major impairment in the behavioral performance of AP2γ KO mice, since all parameters analyzed, including the ones where we found differences, were within the typical range for appearance of the developmental milestones. However, in the juvenile behavior assessment and in the hippocampal glutamatergic neurogenesis process, impairments were found, since AP2γ KO mice showed anxious-like behavior and decreased proliferation of immature neurons. To study the impact of modulating the transcription factor AP2γ in depression we exposed both constitutive and conditional KO animal models to a chronic stress protocol, which efficiently induced core depressive-like symptoms. Through the conditional AP2γ KO mice, we were able to elucidate the impact of deleting AP2γ on behavior and neurogenesis in depressive-like conditions specifically in adult age, without the interference of potential functions of the gene during early development that may appear in the constitutive AP2γ model. Through a multidimensional behavioral analysis, we observed that both models presented similar results in the three most affected behavioral dimensions in depression, namely anxiety, mood and cognition. Regarding anxiety and mood no major differences were found between genotypes in both animal models. Moreover, AP2γ KO mice presented cognitive deficits in basal conditions, but when exposed to chronic mild stress no detrimental effects of deletion of the gene were observed. In this work, we also identified, through a broad analysis of the dentate gyrus neurogenic niche, alterations of epigenetic regulators in the AP2γ constitutive KO mice after uCMS exposure. The reported results not only support the involvement of AP2γ in the transcriptional network that modulates the juvenile and adult neurogenic process, but also highlight the potential of this molecule as a future therapeutical tool in neuropsychiatric disorders, in which neurogenesis is impaired. |
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| Autores principais: | Campos, Eduardo Manuel Loureiro de |
| Assunto: | Ciências Médicas |
| Ano: | 2016 |
| 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: | Major depressive disorder (MDD) is a multidimensional psychiatric disease, considered by the World Health Organization as one of the leading causes of disability. Despite the importance of this disease in modern societies and the large investment of resources already made in its study, the processes underlying its pathophysiology remain poorly understood. Several hypotheses have been proposed to clarify the neurobiological mechanisms underlying this psychiatric disorder, being the link between adult hippocampal neurogenesis and MDD a central topic in the past decades. Previous studies have identified AP2γ as a key regulator of adult hippocampal neurogenesis in mice, being expressed in a subpopulation of adult transient amplifying progenitors, and acting as a regulator of basal progenitors, promoting proliferation and glutamatergic neuronal differentiation. Thus, we wanted to further explore the impact of AP2γ in brain neurophysiology and behavior during development and at adult stages, dissecting also its mechanisms both in healthy and depressive states. With this study, we were able to understand the impact of AP2γ in post-natal development and during juvenile age, through the AP2γ constitutive knockout (KO) model. In the developmental milestones assessment we did not find any major impairment in the behavioral performance of AP2γ KO mice, since all parameters analyzed, including the ones where we found differences, were within the typical range for appearance of the developmental milestones. However, in the juvenile behavior assessment and in the hippocampal glutamatergic neurogenesis process, impairments were found, since AP2γ KO mice showed anxious-like behavior and decreased proliferation of immature neurons. To study the impact of modulating the transcription factor AP2γ in depression we exposed both constitutive and conditional KO animal models to a chronic stress protocol, which efficiently induced core depressive-like symptoms. Through the conditional AP2γ KO mice, we were able to elucidate the impact of deleting AP2γ on behavior and neurogenesis in depressive-like conditions specifically in adult age, without the interference of potential functions of the gene during early development that may appear in the constitutive AP2γ model. Through a multidimensional behavioral analysis, we observed that both models presented similar results in the three most affected behavioral dimensions in depression, namely anxiety, mood and cognition. Regarding anxiety and mood no major differences were found between genotypes in both animal models. Moreover, AP2γ KO mice presented cognitive deficits in basal conditions, but when exposed to chronic mild stress no detrimental effects of deletion of the gene were observed. In this work, we also identified, through a broad analysis of the dentate gyrus neurogenic niche, alterations of epigenetic regulators in the AP2γ constitutive KO mice after uCMS exposure. The reported results not only support the involvement of AP2γ in the transcriptional network that modulates the juvenile and adult neurogenic process, but also highlight the potential of this molecule as a future therapeutical tool in neuropsychiatric disorders, in which neurogenesis is impaired. |
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