Analysis of miR-34a function in brain development and behavior using knockout mouse model / 生理学报

ABSTRACT

miR-34a is a conserved microRNA highly expressed in the brain. It is thought to play critical roles in regulating many aspects of brain development and function, such as neural stem cell proliferation and differentiation, neuronal migration and apoptosis, fear memory consolidation, etc. However, the assessment of its function was mainly conducted through vector-mediated overexpression and miRNA sponge or antagomir-mediated functional suppression, therefore may suffer from nonspecific off-target effects or incomplete inactivation. We thus analyzed mouse model with a targeted deletion of miR-34a which completely abolishes its expression. To our surprise, loss of miR-34a led to neither an obvious change in brain size, morphology or cortical lamination, nor impaired marker gene expression in major excitatory and inhibitory neuron types in the neocortex. In addition, miR-34a ablation did not affect fear memory formation or consolidation, as well as the anxiety or depression related behavior. However, the performance of mice in rotarod assay was significantly affected, suggesting a defect in motor activity in miR-34a deficient mice. As neocortical parvalbumin (PV) neurons are known for high level miR-34a expression, we also tested the effect of PV-Cre-mediated conditional miR-34a deletion. Similar as germline deletion, PV neuron specific miR-34a deletion did not affect cortical lamination or PV expression in the neocortex. Our studies suggest that, although miR-34a may be involved in regulating certain aspects of brain development or function, such as motor activity, it does not play a significant role in regulating brain morphogenesis, cortical lamination or neocortical neuron subtype specification, and it is also dispensable for fear memory formation, expression and consolidation.