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Background  Formation and maintenance of appropriate neural networks require tight regulation of neural stem cell proliferation, differentiation, and neurogenesis. microRNAs (miRNAs) play an important role in brain development and plasticity, and dysregulated miRNA profiles have been linked to neurodevelopmental disorders including autism, schizophrenia, or intellectual disability. Yet, the functional role of miRNAs in neural development and postnatal brain functions remains unclear.    Methods  Using a combination of cell biology techniques as well as behavioral studies and brain imaging, we characterize mouse models with either constitutive inactivation or selectively hippocampal knockdown of the neurodevelopmental disease-associated gene Mir146a, the most commonly deregulated miRNA in developmental brain disorders (DBD).    Results  We first show that during development, loss of  miR-146a  impairs the differentiation of radial glial cells, neurogenesis process, and neurite extension. In the mouse adult brain, loss of  miR-146a  correlates with an increased hippocampal asymmetry coupled with defects in spatial learning and memory performances. Moreover, selective hippocampal downregulation of  miR-146a  in adult mice causes severe hippocampal-dependent memory impairments indicating for the first time a role for this miRNA in postnatal brain functions.    Conclusion  Our results show that  miR-146a  expression is critical for correct differentiation of neural stem cell during brain development and provide for the first time a strong argument for a postnatal role of  miR-146a  in regulating hippocampal-dependent memory. Furthermore, the demonstration that the  Mir146a   −/−   mouse recapitulates several aspects reported in DBD patients, including impaired neurogenesis, abnormal brain anatomy, and working and spatial memories deficits, provides convincing evidence that the dysregulation of  miR146a  contributes to the pathogenesis of DBDs.

Loss of the neurodevelopmental disease-associated gene miR-146a impairs neural progenitor differentiation and causes learning and memory deficits