Impaired motor learning performance in cerebellar En-2 mutant mice.

Gerlai, Robert; Millen, Kathleen J.; Herrup, Karl; Fabien, K.; Joyner, Alexandra L.; Roder, John

doi:10.1037/0735-7044.110.1.126

Cited by 67 publications

(38 citation statements)

References 41 publications

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“…34 The mutant mice are also characterized by hyperactivity, reduced spatial learning 34 and impaired motor coordination. 34,300 Changes in brain morphology include a smaller cerebellum with aberrant foliation and reduced numbers of Purkinje and granule neurons. 301,302 The cerebellar neuropathology emerges during embryonic development of the mutant mice.…”

Section: Genes Responsive To Environmental Factorsmentioning

confidence: 99%

Advances in behavioral genetics: mouse models of autism

2007

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Autism is a neurodevelopmental syndrome with markedly high heritability. The diagnostic indicators of autism are core behavioral symptoms, rather than definitive neuropathological markers. Etiology is thought to involve complex, multigenic interactions and possible environmental contributions. In this review, we focus on genetic pathways with multiple members represented in autism candidate gene lists. Many of these pathways can also be impinged upon by environmental risk factors associated with the disorder. The mouse model system provides a method to experimentally manipulate candidate genes for autism susceptibility, and to use environmental challenges to drive aberrant gene expression and cell pathology early in development. Mouse models for fragile X syndrome, Rett syndrome and other disorders associated with autistic-like behavior have elucidated neuropathology that might underlie the autism phenotype, including abnormalities in synaptic plasticity. Mouse models have also been used to investigate the effects of alterations in signaling pathways on neuronal migration, neurotransmission and brain anatomy, relevant to findings in autistic populations. Advances have included the evaluation of mouse models with behavioral assays designed to reflect disease symptoms, including impaired social interaction, communication deficits and repetitive behaviors, and the symptom onset during the neonatal period. Research focusing on the effect of gene-by-gene interactions or genetic susceptibility to detrimental environmental challenges may further understanding of the complex etiology for autism.

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Section: Genes Responsive To Environmental Factorsmentioning

confidence: 99%

Advances in behavioral genetics: mouse models of autism

2007

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“…In a study of 14 children with autism, they found that abnormal exploratory behavior was significantly associated with the magnitude of the hypoplasia of cerebellar vermal lobules VI and VII. However, a study by Gerlai et al [31] has indicated no difference in exploratory behavior between En2 −/− mice and controls. In this same study, Engrailed-2 mutants performed normally in several tests of motor function, but both hetero-and homozygotes performed below the level of wild type mice in a motor learning paradigm, indicative of a possible learning disability.…”

Section: Engrailed the Cerebellum And Autismmentioning

confidence: 99%

The mouse Engrailed genes: A window into autism

Kuemerle

Gulden

Cherosky

et al. 2007

Behavioural Brain Research

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The complex behavioral symptoms and neuroanatomical abnormalities observed in autistic individuals strongly suggest a multi-factorial basis for this perplexing disease. Although not the perfect model, we believe the Engrailed genes provide an invaluable "window" into the elusive etiology of Autism Spectrum Disorder. The Engrailed-2 gene has been associated with autism in genetic linkage studies. The En2 knock-out mouse harbors cerebellar abnormalities that are similar to those found in autistic individuals and, as we report here, has a distinct anterior shift in the position of the amygdala in the cerebral cortex. Our initial analysis of background effects in the En1 mouse knock-out provides insight as to possible molecular mechanisms and gender differences associated with autism. These findings further the connection between Engrailed and autism and provide new avenues to explore in the ongoing study of the biological basis of this multifaceted disease.

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“…Symptomatic YAC128 mice also showed deficits in open-field habituation, a simple test of learning and memory (Gerlai et al, 1996;Bolivar et al, 2000;Cook et al, 2002). At 8 months of age, YAC128 mice were hypoactive compared with WT mice.…”

Section: Cognitive Deficits In Symptomatic Yac128 Micementioning

confidence: 99%

“…At 2 months of age, YAC128 mice showed a learning deficit on the rotarod test of motor coordination (Lalonde et al, 1995;Gerlai et al, 1996 . YAC128 mice show cognitive deficits in the reversal phase of the swimming T-maze test.…”

Section: Cognitive Deficits In Presymptomatic Yac128 Micementioning

confidence: 99%

Cognitive Dysfunction Precedes Neuropathology and Motor Abnormalities in the YAC128 Mouse Model of Huntington's Disease

Raamsdonk¹,

Pearson²,

Slow³

et al. 2005

J. Neurosci.

287

232

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Huntington's disease (HD) is an adult-onset neurodegenerative disorder involving motor dysfunction, cognitive deficits, and psychiatric disturbances that result from underlying striatal and cortical dysfunction and neuropathology. The YAC128 mouse model of HD reproduces both the motor deficits and selective degeneration observed in the human disease. However, the presence of cognitive impairment in this model has not been determined. Here, we report mild cognitive deficits in YAC128 mice that precede motor onset and progressively worsen with age. Rotarod testing revealed a motor learning deficit at 2 months of age that progresses such that by 12 months of age, untrained YAC128 mice are unable to learn the rotarod task. Additional support for cognitive dysfunction is evident in a simple swimming test in which YAC128 mice take longer to find the platform than wild-type (WT) controls beginning at 8 months of age. YAC128 mice also have deficits in open-field habituation and in a swimming T-maze test at this age. Strikingly, in the reversal phase of the swimming T-maze test, YAC128 mice take twice as long as WT mice to locate the platform, indicating a difficulty in changing strategy. At 12 months of age, YAC128 mice show decreased prepulse inhibition and habituation to acoustic startle. The clear pattern of cognitive dysfunction in YAC128 mice is similar to the symptoms and progression of cognitive deficits in human HD and provides both the opportunity to examine the relationship between cognitive dysfunction, motor impairment, and neuropathology in HD and to assess whether potential therapies for HD can restore cognitive function.

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Impaired motor learning performance in cerebellar En-2 mutant mice.

Cited by 67 publications

References 41 publications

Advances in behavioral genetics: mouse models of autism

Advances in behavioral genetics: mouse models of autism

The mouse Engrailed genes: A window into autism

Cognitive Dysfunction Precedes Neuropathology and Motor Abnormalities in the YAC128 Mouse Model of Huntington's Disease

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