RT Journal Article
SR Electronic
T1 The Pattern of Cortical Dysfunction in a Mouse Model of a Schizophrenia-Related Microdeletion
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 14825
OP 14839
DO 10.1523/JNEUROSCI.1611-13.2013
VO 33
IS 37
A1 Karine Fénelon
A1 Bin Xu
A1 Cora S. Lai
A1 Jun Mukai
A1 Sander Markx
A1 Kimberly L. Stark
A1 Pei-Ken Hsu
A1 Wen-Biao Gan
A1 Gerald D. Fischbach
A1 Amy B. MacDermott
A1 Maria Karayiorgou
A1 Joseph A. Gogos
YR 2013
UL http://www.jneurosci.org/content/33/37/14825.abstract
AB 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.