Abstract
The 22q11.2 deletion is the strongest known genetic risk factor for schizophrenia. Research has implicated microRNA-mediated dysregulation in 22q11.2 deletion syndrome (22q11.2DS) schizophrenia-risk. Primary candidate genes are DGCR8 (DiGeorge syndrome critical region gene 8), which encodes a component of the microprocessor complex essential for microRNA biogenesis, and MIR185, which encodes microRNA 185. Mouse models of 22q11.2DS have demonstrated alterations in brain microRNA biogenesis, and that DGCR8 haploinsufficiency may contribute to these alterations, e.g., via down-regulation of a specific microRNA subset. miR-185 was the top-scoring down-regulated microRNA in both the prefrontal cortex and the hippocampus, brain areas which are the key foci of schizophrenia research. This reduction in miR-185 expression contributed to dendritic and spine development deficits in hippocampal neurons. In addition, miR-185 has two validated targets (RhoA, Cdc42), both of which have been associated with altered expression levels in schizophrenia. These combined data support the involvement of miR-185 and its down-stream pathways in schizophrenia. This review summarizes evidence implicating microRNA-mediated dysregulation in schizophrenia in both 22q11.2DS-related and idiopathic cases.
Highlights
The 22q11.2 deletion syndrome (22q11.2DS), known as the velocardiofacial/DiGeorge syndrome, is a phenotypically heterogenous disease which is caused by a hemizygous microdeletion on the long arm of chromosome 22 in the region q11.2
Primary candidate genes are DGCR8 (DiGeorge syndrome critical region gene 8), which encodes a component of the microprocessor complex essential for microRNA biogenesis, and MIR185, which encodes microRNA 185
Mouse models of 22q11.2DS have demonstrated alterations in brain microRNA biogenesis, and that DGCR8 haploinsufficiency may contribute to these alterations, e.g., via downregulation of a specific microRNA subset. miR-185 was the top-scoring down-regulated microRNA in both the prefrontal cortex and the hippocampus, brain areas which are the key foci of schizophrenia research
Summary
The 22q11.2 deletion syndrome (22q11.2DS), known as the velocardiofacial/DiGeorge syndrome, is a phenotypically heterogenous disease which is caused by a hemizygous microdeletion on the long arm of chromosome 22 in the region q11.2. Schofield et al (2011) identified alterations in the electrical properties of layer V pyramidal neurons in the medial PFC of Dgcr8+/− mice, as well as a decrease in the complexity of the basal dendrites and reduced excitatory synaptic transmission These functional results suggest that precise microRNA expression is critical for the development of PFC circuitry (Schofield et al, 2011), circuitry which has been reported to be altered in schizophrenia patients (Ursu et al, 2011). Dgcr8+/− mice displayed a decrease in the number of cortical neurons, structural deficits in dendritic spines in the PFC, and alterations in synaptic potentiation and short-term plasticity (Fenelon et al, 2011) These alterations might influence functional connectivity (Schreiner et al, 2013), and could be implicated in the observed cognitive and behavioral deficits. Restoration of IGF2 expression in the hippocampus rescued the observed spatial working memory deficits in Dgcr8+/− mice, suggesting that IGF2 contributes – at least in part – to the learning and spatial working memory deficits that are associated with 22q11.2DS-related schizophrenia (Ouchi et al, 2013)
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