The pattern of cortical dysfunction in a mouse model of a schizophrenia-related microdeletion

J Neurosci. 2013 Sep 11;33(37):14825-39. doi: 10.1523/JNEUROSCI.1611-13.2013.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cognition Disorders / etiology
  • Cognition Disorders / genetics
  • Dendritic Spines / pathology
  • Dendritic Spines / ultrastructure
  • DiGeorge Syndrome / complications
  • DiGeorge Syndrome / genetics
  • DiGeorge Syndrome / pathology*
  • Disease Models, Animal
  • Gene Expression Regulation / genetics
  • Gene Regulatory Networks / genetics
  • In Vitro Techniques
  • Long-Term Potentiation / genetics*
  • Long-Term Synaptic Depression / genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neurons / pathology
  • Neurons / physiology*
  • Phosphopyruvate Hydratase / metabolism
  • Prefrontal Cortex / pathology*
  • Proteins / genetics
  • RNA-Binding Proteins
  • Recognition, Psychology / physiology
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / genetics
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism


  • Dgcr8 protein, mouse
  • Proteins
  • RNA-Binding Proteins
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Phosphopyruvate Hydratase
  • Atp2a2 protein, mouse