The Pattern of Cortical Dysfunction in a Mouse Model of a Schizophrenia-Related Microdeletion

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.

Loss-of-function mutation in Mirta22/Emc10 rescues specific schizophrenia-related phenotypes in a mouse model of the 22q11.2 deletion

“…We have previously shown that Df(16)A +/− mice exhibit a robust PPI deficit (12). Analysis by genotype [repeated measures (RM) ANOVA, prepulse × genotype interaction F(12, 224) = 1.981, P = 0.027; main effect of genotype F(3, 56) = 8.308, P < 0.001] confirmed our previous result [Df (16)A +/− vs. WT, Bonferroni post hoc analysis, P < 0.0001; Fig. 1A Fig.…”

“…Specifically, the mice exhibit hyperactivity, decrease in prepulse inhibition (PPI) that is indicative of sensorimotor gating deficits, working memory (WM) abnormalities, social memory (SM) deficits, and associative (fear) memory deficits (12). In addition to the observed behavioral abnormalities, Df(16)A +/− mice also show alterations in the dendritic development of cortical neurons, as well as deficits in several forms of prefrontal cortical synaptic plasticity, which also emerge in part due to miRNA dysregulation (16). If the sustained postnatal elevation of Mirta22 levels hinders normal development of circuits and behaviors, one prediction would be that LoF mutations of Mirta22 will have beneficial effects, preventing the emergence of at least some of these deficits.…”

“…Specifically, previous research on the 22q11.2 deletions provided one of the strongest initial indications for a link between miRNA dysregulation and SCZ risk (12,13). A mouse model carrying a hemizygous 1.3-Mb chromosomal deficiency on chromosome 16 [Df (16)A], which is syntenic to the human 1.5-Mb 22q11.2 microdeletion, demonstrates abnormal processing and levels of brain miRNAs (12). This miRNA dysregulation is due to hemizygosity of DGCR8, a component of the "microprocessor" complex that is essential for miRNA production, as well as hemizygosity of miRNA genes residing within the deletion, most notably mir185 (12,14,15).…”

Epilepsy and Autism

“…ELS also have been shown to increase short-term plasticity in the mesial prefrontal cortex (mPFC) (Hernan et al 2013). Alterations in short-term plasticity in the mPFC have been associated with changes in hippocampal-PFC synchrony (Sigurdsson et al 2010;Fenelon et al 2013). Taken together, these findings suggest there is a long-standing increase in the E/I ratio in the mPFC.…”

Intravital imaging of dendritic spine plasticity

“…Increases in spine formation and elimination have been found in animal models for Fragile X syndrome, 50,51 Rett syndrome 52 and schizophrenia. 53 In neurodegenerative disease models, similar increases of spine turnover are observed and it will follow by subsequent net loss of spines, for example, in Alzheimer disease, 54,55 prion disease 56 and Huntington disease. 57 In the stroke model, severe ischemia caused a rapid loss of spine and dendrite structure within 10 minutes.…”