MicroRNA-132 dysregulation in schizophrenia has implications for both neurodevelopment and adult brain function.
Schizophrenia is characterized by affective, cognitive, neuromorphological, and molecular abnormalities that may have a neurodevelopmental origin. MicroRNAs (miRNAs) are small noncoding RNA sequences critical to neurodevelopment and adult neuronal processes by coordinating the activity of multiple genes within biological networks. We examined the expression of 854 miRNAs in prefrontal cortical tissue from 100 control, schizophrenic, and bipolar subjects. The cyclic AMP-responsive element binding- and NMDA-regulated microRNA miR-132 was significantly down-regulated in both the schizophrenic discovery cohort and a second, independent set of schizophrenic subjects. Analysis of miR-132 target gene expression in schizophrenia gene-expression microarrays identified 26 genes up-regulated in schizophrenia subjects. Consistent with NMDA-mediated hypofunction observed in schizophrenic subjects, administration of an NMDA antagonist to adult mice results in miR-132 down-regulation in the prefrontal cortex. Furthermore, miR-132 expression in the murine prefrontal cortex exhibits significant developmental regulation and overlaps with critical neurodevelopmental processes during adolescence. Adult prefrontal expression of miR-132 can be down-regulated by pharmacologic inhibition of NMDA receptor signaling during a brief postnatal period. Several key genes, including DNMT3A, GATA2, and DPYSL3, are regulated by miR-132 and exhibited altered expression either during normal neurodevelopment or in tissue from adult schizophrenic subjects. Our data suggest miR-132 dysregulation and subsequent abnormal expression of miR-132 target genes contribute to the neurodevelopmental and neuromorphological pathologies present in schizophrenia.
Department of Molecular Therapeutics, The Scripps Research Institute-Scripps Florida, Jupiter, FL 33458, USA.
Brooke H
BH
Miller
Zane
Z
Zeier
Li
L
Xi
Thomas A
TA
Lanz
Shibing
S
Deng
Julia
J
Strathmann
David
D
Willoughby
Paul J
PJ
Kenny
John D
JD
Elsworth
Matthew S
MS
Lawrence
Robert H
RH
Roth
Dieter
D
Edbauer
Robin J
RJ
Kleiman
Claes
C
Wahlestedt
D000328:Adult; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D001921:Brain / Q000187:drug effects / Q000254:growth & development* / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D000090205:DNA Methyltransferase 3A; D030541:Databases, Genetic; D003710:Demography; D004195:Disease Models, Animal; D050989:GATA2 Transcription Factor / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D016202:N-Methylaspartate / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016366:Open Reading Frames / Q000235:genetics; D016133:Polymerase Chain Reaction; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015203:Reproducibility of Results; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects
D014150:Antipsychotic Agents; C000717967:DNMT3A protein, human; C102926:DPYSL3 protein, human; C000715535:Dnmt3a protein, mouse; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; C547077:MIRN132 microRNA, human; D035683:MicroRNAs; D009124:Muscle Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A