![]() ![]() Importantly, there are no major clinical differences in the core SCZ phenotype between individuals with SCZ who are 22q11.2 microdeletion carriers and those who are not ( Bassett et al., 1998, 2003 Karayiorgou et al., 2010). Recurrent 22q11.2 deletions account for as many as 1–2% of cases of sporadic SCZ ( Karayiorgou et al., 1995 Xu et al., 2008) and exemplify the important contribution of rare mutations to disease susceptibility ( Xu et al., 2008, 2012a Rodriguez-Murillo et al., 2012). They also provide insight into the link between micro-RNA dysregulation and genetic liability to schizophrenia and cognitive dysfunction.Ĭarriers of deletions in chromosome 22q11.2, which predominantly occur de novo, exhibit a spectrum of cognitive deficits in children ( Kates et al., 2007) and develop into schizophrenia (SCZ) in adulthood at a rate of 25–30% ( Karayiorgou et al., 2010). Our findings inform the cortical synaptic and neuronal mechanisms of working memory impairment in the context of psychiatric disorders. 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. 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. 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. 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. 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.
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