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The pattern of cortical dysfunction in a mouse model of a schizophrenia-related microdeletion.
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2013 Sep 11; Vol. 33 (37), pp. 14825-39. - Publication Year :
- 2013
-
Abstract
- We used a mouse model of the schizophrenia-predisposing 22q11.2 microdeletion to evaluate how this genetic lesion affects cortical neural circuits at the synaptic, cellular, and molecular levels. Guided by cognitive deficits, we demonstrated that mutant mice display robust deficits in high-frequency synaptic transmission and short-term plasticity (synaptic depression and potentiation), as well as alterations in long-term plasticity and dendritic spine stability. Apart from previously reported reduction in dendritic complexity of layer 5 pyramidal neurons, altered synaptic plasticity occurs in the context of relatively circumscribed and often subtle cytoarchitectural changes in neuronal density and inhibitory neuron numbers. We confirmed the pronounced DiGeorge critical region 8 (Dgcr8)-dependent deficits in primary micro-RNA processing and identified additional changes in gene expression and RNA splicing that may underlie the effects of this mutation. Reduction in Dgcr8 levels appears to be a major driver of altered short-term synaptic plasticity in prefrontal cortex and working memory but not of long-term plasticity and cytoarchitecture. Our findings inform the cortical synaptic and neuronal mechanisms of working memory impairment in the context of psychiatric disorders. They also provide insight into the link between micro-RNA dysregulation and genetic liability to schizophrenia and cognitive dysfunction.
- Subjects :
- Animals
Cognition Disorders etiology
Cognition Disorders genetics
Dendritic Spines pathology
Dendritic Spines ultrastructure
DiGeorge Syndrome complications
DiGeorge Syndrome genetics
Disease Models, Animal
Gene Expression Regulation genetics
Gene Regulatory Networks genetics
In Vitro Techniques
Male
Mice
Mice, Inbred C57BL
Neurons pathology
Phosphopyruvate Hydratase metabolism
Proteins genetics
RNA-Binding Proteins
Recognition, Psychology physiology
Sarcoplasmic Reticulum Calcium-Transporting ATPases genetics
Sarcoplasmic Reticulum Calcium-Transporting ATPases metabolism
DiGeorge Syndrome pathology
Long-Term Potentiation genetics
Long-Term Synaptic Depression genetics
Neurons physiology
Prefrontal Cortex pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1529-2401
- Volume :
- 33
- Issue :
- 37
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 24027283
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.1611-13.2013