MiR-124 dosage regulates prefrontal cortex function by dopaminergic modulation

Takashi Kozuka,Mayu Furuhashi,Haruka Yamamoto,Satoshi Watanabe,Makiko Morita,Etsuko Tarusawa,Takatoshi Hikida,Yumiko Yoshimura,Shinichi Hirose,Takahisa Furukawa,Tetsuya Sato,Taro Chaya,Yoshihiro Omori,Yasuyuki Ohkawa

doi:10.1038/s41598-019-38910-2

Abstract

MicroRNA-124 (miR-124) is evolutionarily highly conserved among species and one of the most abundantly expressed miRNAs in the developing and mature central nervous system (CNS). Previous studies reported that miR-124 plays a role in CNS development, such as neuronal differentiation, maturation, and survival. However, the role of miR-124 in normal brain function has not yet been revealed. Here, we subjected miR-124-1+/− mice, to a comprehensive behavioral battery. We found that miR-124-1+/− 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 miR-124-1+/− 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 Drd2 expression level in the miR-124-1+/− PFC. Overexpression or knockdown of Drd2 in the control or miR-124-1+/− PFC demonstrates that aberrant Drd2 signaling leads to impaired PPI. Furthermore, we identified that expression of glucocorticoid receptor gene Nr3c1, which enhances Drd2 expression, increased in the miR-124-1+/− PFC. Taken together, the current study suggests that miR-124 dosage modulates PFC function through repressing the Drd2 pathway, suggesting a critical role of miR-124 in normal PFC function.

Highlights

MicroRNAs are small non-coding RNA molecules regulating gene expression of a great variety of biological processes in plants and animals
To examine whether miR-124-1+/− mice show dopamine-associated behavioral deficits, we investigated the response of miR-124-1+/− mice to methamphetamine using the open field
We found that the distance traveled by miR-124-1+/− mice in the open field test increased significantly compared to WT mice after methamphetamine administration (Fig. 2d; two-way repeated-measures ANOVA: Genotype: F(1, 13) = 6.714, p = 0.0224; Time: F(12, 156) = 4.304, p < 0.0001; Interaction: F(12, 156) = 6.334, p < 0.0001)

Summary

Introduction

MicroRNAs (miRNAs) are small non-coding RNA molecules regulating gene expression of a great variety of biological processes in plants and animals. The nucleotide sequence of miR-124 and its nervous system-specific expression pattern are highly evolutionarily conserved from C. elegans through Drosophila melanogaster, and all vertebrates studied through to humans. Both in human and mouse genomes, miR-124s are encoded on three loci: miR-124-1, -2, and -3. Consistent with its expression pattern in the developing CNS, miR-124 has been reported to be essential for neuronal differentiation[7,8], maturation[2,9,10,11], synaptic plasticity[12,13] and progenitor proliferation[7], it should be noted that conflicting results on miR-124 function have been reported. We investigated the role and mechanism of miR-124 in normal brain functions using miR-124-1+/− mice

Methods

Results

Conclusion