Experience-dependent expression of miR-132 regulates ocular dominance plasticity

Abstract

miR-132 is a CREB-induced microRNA that is involved in dendritic spine plasticity. We found that visual experience regulated histone post-translational modifications at a CRE locus that is important for miR-212 and miR-132 cluster transcription, and regulated miR-132 expression in the visual cortex of juvenile mice. Monocular deprivation reduced miR-132 expression in the cortex contralateral to the deprived eye. Counteracting this miR-132 reduction with an infusion of chemically modified miR-132 mimic oligonucleotides completely blocked ocular dominance plasticity.

Fig. 1. Visual stimulation induces histone mark modifications on specific CRE loci close to miR132 coding sequence and activates mature and primary miR132 expression

a) Ac(Lys9-14)H3 ChIP showed visually-induced H3 acetylation at the CRE loci upstream of miR132, miR212 and fos. * p<0.05. b) p(Ser10)Ac(Lys14)H3 ChIP showed visually-induced H3 phosphoacetylation at the CRE sequences upstream of miR132 and fos, but not miR212. c) Me2(Lys4)H3 ChIP showed visually-induced H3 dimethylation at the CRE sequence upstream of miR132 and fos, but not miR212. d) Developmental expression of pri-miR132 and miR132 in the visual cortex of STR and DRB mice. Pri-miR132 (left) and miR132 (right) expression significantly increased with age in STR but not in DRB mice. * represents significant differences between STR and DRB. e) DR3d decreased pri-miR132 (left) and miR132 (right) in visual cortex respect to age matched mice (P27 STR). f) Visual stimulation after DR3d increased pri-miR132 (left) and miR132 (right) levels. Data are reported as mean ± SEM.

Fig. 2. MiR132 downregulation after monocular deprivation regulates ODP in juvenile mice

a) Decreased p(Ser10)Ac(Lys14)H3 at CREmiR132 in the binocular visual cortex contralateral (left ctx contra) to the deprived eye with respect to the ipsilateral cortex (right ctx ipsi) in MD3d mice (n=13, p(Ser10)Ac(Lys14)H3, right ctx ipsi vs left ctx contra paired t test p=0.015; Ac(Lys9–14)H3, right ctx ipsi vs left ctx contra signed rank test p=0.3; Me2(Lys4)H3 n=16, paired t test p=0.07). b) MD3d decreased pri-miR132 (left) and miR132 (right) expression in the binocular visual cortex contralateral to the deprived eye. c) ISH for mature miR132 in MD3d mice showed a reduction in the cortex contralateral to the deprived eye (bar = 100 micron). MiR132 positive cell density in nondeprived mice (shaded area, average ± SEM, n=4) was not different from MD3d mice (t-test, p>0.05). d) Cumulative distribution of ODS in nondeprived (N=6, n=103 cells), MD3d (N=5, n=83), MD3d treated with miR132 mimic (N=5, n=79 cells), and MD3d treated with control miRNA (control miR) mice (N=5, n=95 cells). e) CBI of nondeprived (n=6), MD3d (n=5), MD3d miR132 mimic (n=5), and MD3d control miR (n=5) mice. Open circles = single animal data, black circles = average CBI ± SEM. Mice N as in d. f) C/I VEP ratio of nondeprived (n=5), MD3d (n=4), MD3d miR132 mimic (n=5), and MD3d control miR (n=5) mice. Open circles = single animal data, black circles = average ratio ± SEM. Error bars=SEM in a,b,c.