RESUMO
Physical exercise in combination with cognitive training is known to enhance synaptic plasticity, learning, and memory and lower the risk for various complex diseases including Alzheimer's disease. Here, we show that exposure of adult male mice to an environmental enrichment paradigm leads to enhancement of synaptic plasticity and cognition also in the next generation. We show that this effect is mediated through sperm RNA and especially miRs 212/132. In conclusion, our study reports intergenerational inheritance of an acquired cognitive benefit and points to specific miRs as candidates mechanistically involved in this type of transmission.
Assuntos
Plasticidade Neuronal/fisiologia , Condicionamento Físico Animal , RNA/metabolismo , Animais , Comportamento Animal , Encéfalo/metabolismo , Cognição/fisiologia , Potenciais Pós-Sinápticos Excitadores , Hipocampo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/química , MicroRNAs/metabolismo , RNA/química , RNA/isolamento & purificação , Análise de Sequência de RNA , Meio Social , Espermatozoides/metabolismoRESUMO
Learning and memory are cognitive processes that are tightly regulated. A proper genome-environment interaction is a pre-requisite for cognitive function. Epigenetic processes are central regulators of genome-environment interactions. In line with this, it has been shown that the epigenetic machinery is essential for cognitive function. With a specific focus on histone acetylation, we will discuss recent research in the field of epigenetic mechanisms of learning and memory. We will also specifically address the role of histone acetylation in age-associated memory impairment and Alzheimer's disease and ask the question why targeting the epigenome could be a suitable strategy for neuroprotection and neuroregeneration.
Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Histonas/metabolismo , Transtornos da Memória/metabolismo , Acetilação , Fatores Etários , Envelhecimento/genética , Doença de Alzheimer/genética , Epigênese Genética , Histonas/genética , Humanos , Memória/fisiologia , Transtornos da Memória/genéticaRESUMO
Learning and memory processes critically involve the orchestrated regulation of de novo protein synthesis. On the other hand it has become clear that regulated protein degradation also plays a major role in neuronal plasticity and learning behavior. One of the key pathways mediating protein degradation is proteosomal protein destruction. The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that targets proteins for proteosomal degradation by the 26S proteasome. While the APC/C is essential for cell cycle progression it is also expressed in postmitotic neurons where it has been implicated with axonal outgrowth and neuronal survival. In this study we addressed the role of APC/C in learning and memory function by generating mice that lack the essential subunit APC2 from excitatory neurons of the adult forebrain. Those animals are viable but exhibit a severe impairment in the ability to extinct fear memories, a process critical for the treatment of anxiety diseases such as phobia or post-traumatic stress disorder. Since deregulated protein degradation and APC/C activity has been implicated with neurodegeneration we also analyzed the effect of Apc2 deletion in a mouse model for Alzheimer's disease. In our experimental setting loss of APC2 form principle forebrain neurons did not affect the course of pathology in an Alzheimer's disease mouse model. In conclusion, our data provides genetic evidence that APC/C activity in the adult forebrain is required for cognitive function.
