Derepression of a Neuronal Inhibitor due to miRNA Dysregulation in a Schizophrenia-Related Microdeletion
Open accessAbstract
22q11.2 microdeletions result in specific cognitive deficits and schizophrenia. Analysis of Df(16)A(+/-) mice, which model this microdeletion, revealed abnormalities in the formation of neuronal dendrites and spines, as well as altered brain microRNAs. Here, we show a drastic reduction of miR-185, which resides within the 22q11.2 locus, to levels more than expected by a hemizygous deletion, and we demonstrate that this reduction alters dendritic and spine development. miR-185 represses, through an evolutionarily conserved target site, a previously unknown inhibitor of these processes that resides in the Golgi apparatus and shows higher prenatal brain expression. Sustained derepression of this inhibitor after birth represents the most robust transcriptional disturbance in the brains of Df(16)A(+/-) mice and results in structural alterations in the hippocampus. Reduction of miR-185 also has milder age- and region-specific effects on the expression of some Golgi-related genes. Our findings illuminate the contribution of microRNAs in psychiatric disorders and cognitive dysfunction.
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Reduced miR-185 expression caused deficits in dendritic complexity and spine development in hippocampal neurons, possibly mediated by increased RhoA expression.
“The reduced miR-185 expression caused deficits in dendritic complexity and spine development in hippocampal neurons [108], possibly mediated by increased RhoA expression as the two validated miR-185 targets, RhoA and Cdc42 [109], have altered expression levels in schizophrenia [110,111,112].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [108]
In the medial prefrontal cortex of Df(16)A+/− mice, there is a decrease in cell numbers in layers II and V, with fewer inhibitory neurons in layer V; cell size is normal, basal dendritic length and complexity are decreased, and the length of the primary apical dendrite is reduced.
“In the medial prefrontal cortex of Df(16)A+/− mice, there is a decrease in cell numbers in layers II and V, with fewer inhibitory neurons in layer V. Cell size is normal, basal dendritic length and complexity is decreased [391] and length of the primary apical dendrite is reduced in these animals.”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [391]
In Df(16)A+/− mice, spine turnover is higher than in wild-type, with smaller spine width but comparable spine density and length on apical dendrites, and decreased spine density, increased spine width, and fewer mushroom spines on basal dendrites.
“Spine turnover in these animals is higher than in WT, with smaller spine width but comparable spine density and length on apical dendrites [112] and decreased spine density, increased spine width and fewer mushroom spines on the basal dendrites [391].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [391]
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- Authors
- Xu, B., Hsu, P.-K., Stark, K. L., Karayiorgou, M., & Gogos, J. A.
- Affiliations
- Columbia University (US)
- Corresponding author
- Karayiorgou, Maria
- Gogos, Joseph A.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 152
- Issue
- 1-2
- Pages
- 262-275
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3556818
- OpenAlex
- W2023279442
- Cited by
- 145
- References
- 54
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 9 · 2023: 5 · 2022: 10 · 2021: 7 · 2020: 12 · 2019: 8 · 2018: 12 · 2017: 12 · 2016: 10 · 2015: 16 · 2014: 20 · 2013: 14
- FWCI
- 7.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (MH97879, R01MH067068, R01MH077235, MH 67068, R01MH097879, MH077235)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- 22q11.2 microdeletion, schizophrenia, miR-185, microRNA dysregulation, dendrite formation, dendritic spines, Golgi apparatus, transcriptional derepression, hippocampus, cognitive impairment, mental illness, postnatal brain development
- MeSH terms
- Amino Acid Sequence, Animals, Brain, Chromosome Deletion, Chromosomes, Human, Pair 22, Disease Models, Animal, Embryo, Mammalian, Golgi Apparatus, Hippocampus, Humans, Membrane Proteins, Molecular Sequence Data, Neuronal Plasticity, Neurons, Proteins, RNA-Binding Proteins, MicroRNAs, Mice
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