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Previous studies reported that <jats:italic>miR-124<\/jats:italic> plays a role in CNS development, such as neuronal differentiation, maturation, and survival. However, the role of <jats:italic>miR-124<\/jats:italic> in normal brain function has not yet been revealed. Here, we subjected <jats:italic>miR-124-1<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> mice, to a comprehensive behavioral battery. We found that <jats:italic>miR-124-1<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> mice showed impaired prepulse inhibition (PPI), methamphetamine-induced hyperactivity, and social deficits. Whole cell recordings using prefrontal cortex (PFC) slices showed enhanced synaptic transmission in layer 5 pyramidal cells in the <jats:italic>miR-124-1<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> PFC. Based on the results of behavioral and electrophysiological analysis, we focused on genes involved in the dopaminergic system and identified a significant increase of <jats:italic>Drd2<\/jats:italic> expression level in the <jats:italic>miR-124-1<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> PFC. Overexpression or knockdown of <jats:italic>Drd2<\/jats:italic> in the control or <jats:italic>miR-124-1<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> PFC demonstrates that aberrant <jats:italic>Drd2<\/jats:italic> signaling leads to impaired PPI. Furthermore, we identified that expression of glucocorticoid receptor gene <jats:italic>Nr3c1<\/jats:italic>, which enhances <jats:italic>Drd2<\/jats:italic> expression, increased in the <jats:italic>miR-124-1<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> PFC. Taken together, the current study suggests that <jats:italic>miR-124<\/jats:italic> dosage modulates PFC function through repressing the <jats:italic>Drd2<\/jats:italic> pathway, suggesting a critical role of <jats:italic>miR-124<\/jats:italic> in normal PFC function.<\/jats:p>","DOI":"10.1038\/s41598-019-38910-2","type":"journal-article","created":{"date-parts":[[2019,3,5]],"date-time":"2019-03-05T11:05:48Z","timestamp":1551783948000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["miR-124 dosage regulates prefrontal cortex function by dopaminergic modulation"],"prefix":"10.1038","volume":"9","author":[{"given":"Takashi","family":"Kozuka","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1208-1237","authenticated-orcid":false,"given":"Yoshihiro","family":"Omori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etsuko","family":"Tarusawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruka","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taro","family":"Chaya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayu","family":"Furuhashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makiko","family":"Morita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuya","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichi","family":"Hirose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6440-9954","authenticated-orcid":false,"given":"Yasuyuki","family":"Ohkawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumiko","family":"Yoshimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takatoshi","family":"Hikida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahisa","family":"Furukawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,3,5]]},"reference":[{"key":"38910_CR1","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1016\/S0960-9822(02)00809-6","volume":"12","author":"M Lagos-Quintana","year":"2002","unstructured":"Lagos-Quintana, M. et al. Identification of tissue-specific microRNAs from mouse. Curr Biol 12, 735\u2013739 (2002).","journal-title":"Curr Biol"},{"key":"38910_CR2","doi-asserted-by":"publisher","first-page":"1125","DOI":"10.1038\/nn.2897","volume":"14","author":"R Sanuki","year":"2011","unstructured":"Sanuki, R. et al. miR-124a is required for hippocampal axogenesis and retinal cone survival through Lhx2 suppression. Nat Neurosci 14, 1125\u20131134, https:\/\/doi.org\/10.1038\/nn.2897 (2011).","journal-title":"Nat Neurosci"},{"key":"38910_CR3","doi-asserted-by":"publisher","first-page":"e215","DOI":"10.1371\/journal.pgen.0030215","volume":"3","author":"EA Miska","year":"2007","unstructured":"Miska, E. A. et al. Most Caenorhabditis elegans microRNAs are individually not essential for development or viability. 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