Autism-Relevant Social Abnormalities and Cognitive Deficits in Engrailed-2 Knockout Mice

被引:128
作者
Brielmaier, Jennifer [1 ]
Matteson, Paul G. [2 ]
Silverman, Jill L. [1 ]
Senerth, Julia M. [1 ]
Kelly, Samantha [2 ]
Genestine, Matthieu [3 ]
Millonig, James H. [2 ,3 ]
DiCicco-Bloom, Emanuel [3 ]
Crawley, Jacqueline N. [1 ]
机构
[1] NIMH, Lab Behav Neurosci, Bethesda, MD 20892 USA
[2] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA
[3] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, New Brunswick, NJ USA
关键词
HOMEOBOX-TRANSCRIPTION-FACTOR; SENSORIMOTOR GATING DEFICITS; INBRED MOUSE STRAINS; FORCED SWIMMING TEST; TAIL SUSPENSION TEST; MUTANT MICE; PREPULSE INHIBITION; SPECTRUM-DISORDER; BEHAVIORAL PHENOTYPES; ASPERGER-SYNDROME;
D O I
10.1371/journal.pone.0040914
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
ENGRAILED 2 (En2), a homeobox transcription factor, functions as a patterning gene in the early development and connectivity of rodent hindbrain and cerebellum, and regulates neurogenesis and development of monoaminergic pathways. To further understand the neurobiological functions of En2, we conducted neuroanatomical expression profiling of En2 wildtype mice. RTQPCR assays demonstrated that En2 is expressed in adult brain structures including the somatosensory cortex, hippocampus, striatum, thalamus, hypothalamus and brainstem. Human genetic studies indicate that EN2 is associated with autism. To determine the consequences of En2 mutations on mouse behaviors, including outcomes potentially relevant to autism, we conducted comprehensive phenotyping of social, communication, repetitive, and cognitive behaviors. En2 null mutants exhibited robust deficits in reciprocal social interactions as juveniles and adults, and absence of sociability in adults, replicated in two independent cohorts. Fear conditioning and water maze learning were impaired in En2 null mutants. High immobility in the forced swim test, reduced prepulse inhibition, mild motor coordination impairments and reduced grip strength were detected in En2 null mutants. No genotype differences were found on measures of ultrasonic vocalizations in social contexts, and no stereotyped or repetitive behaviors were observed. Developmental milestones, general health, olfactory abilities, exploratory locomotor activity, anxiety-like behaviors and pain responses did not differ across genotypes, indicating that the behavioral abnormalities detected in En2 null mutants were not attributable to physical or procedural confounds. Our findings provide new insight into the role of En2 in complex behaviors and suggest that disturbances in En2 signaling may contribute to neuropsychiatric disorders marked by social and cognitive deficits, including autism spectrum disorders.
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页数:27
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