NMD‐deficient Upf3b‐null mice display behavioral and neuropathological defects

Abstract

To address the physiological role of nonsense‐mediated RNA decay (NMD), we generated mice with a null mutation in the Upf3b NMD gene. While these Upf3b‐null mice are viable, fertile, and grossly normal, a battery of behavioral tests revealed they exhibit a specific defect in sensorimotor gating. This defect is commonly displayed in Schizophrenia patients, a subset of whom have recently been shown by several groups to have mutations in the human UPF3B gene. Neuropathological examination of the frontal cortex, the site responsible for sensorimotor gating, revealed decreased dendritic spine density and mature dendritic spines in pyramidal cells. Intriguingly, such defects are also observed in schizophrenic and autistic patients. To understand the underlying mechanisms by which UPF3B acts in this circuit, we performed exon‐array analysis of the frontal cortex of Upf3b‐null mice. This revealed dysregulation of several mRNAs transcribed from genes mutated in intellectual disability patients, most of which encode proteins that function in sensory perception and cognition. NMD is likely to have a direct role in regulating many of these transcripts, as most have “NMD‐inducing features.” We propose that Upf3b‐null mice are a useful model system to understand the underlying mechanism of sensorimotor gating and how it is disrupted in Schizophrenia patients.This study was supported by the NIH.