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The Journal of Neuroscience, July 8, 2009, 29(27):8752-8763; doi:10.1523/JNEUROSCI.0915-09.2009

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Neurobiology of Disease
A Triplet Repeat Expansion Genetic Mouse Model of Infantile Spasms Syndrome, Arx^(GCG)10+7, with Interneuronopathy, Spasms in Infancy, Persistent Seizures, and Adult Cognitive and Behavioral Impairment

Maureen G. Price,¹ Jong W. Yoo,¹ Daniel L. Burgess,¹ Fang Deng,¹ Richard A. Hrachovy,¹ James D. Frost Jr,¹ and Jeffrey L. Noebels^1,2,3

¹Departments of Neurology, ²Molecular and Human Genetics, and ³Neuroscience, Baylor College of Medicine, Houston, Texas 77030

Correspondence should be addressed to Dr. Jeffrey L. Noebels, Department of Neurology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Email: jnoebels{at}bcm.edu

Infantile spasms syndrome (ISS) is a catastrophic pediatric epilepsy with motor spasms, persistent seizures, mental retardation, and in some cases, autism. One of its monogenic causes is an insertion mutation [c.304ins (GCG)₇] on the X chromosome, expanding the first polyalanine tract of the interneuron-specific transcription factor Aristaless-related homeobox (ARX) from 16 to 23 alanine codons. Null mutation of the Arx gene impairs GABA and cholinergic interneuronal migration but results in a neonatal lethal phenotype. We developed the first viable genetic mouse model of ISS that spontaneously recapitulates salient phenotypic features of the human triplet repeat expansion mutation. Arx^(GCG)10+7 ("Arx plus 7") pups display abnormal spasm-like myoclonus and other key EEG features, including multifocal spikes, electrodecremental episodes, and spontaneous seizures persisting into maturity. The neurobehavioral profile of Arx mutants was remarkable for lowered anxiety, impaired associative learning, and abnormal social interaction. Laminar decreases of Arx+ cortical interneurons and a selective reduction of calbindin-, but not parvalbumin- or calretinin-expressing interneurons in neocortical layers and hippocampus indicate that specific classes of synaptic inhibition are missing from the adult forebrain, providing a basis for the seizures and cognitive disorder. A significant reduction of calbindin-, NPY (neuropeptide Y)-expressing, and cholinergic interneurons in the mutant striatum suggest that dysinhibition within this network may contribute to the dyskinetic motor spasms. This mouse model narrows the range of critical pathogenic elements within brain inhibitory networks essential to recreate this complex neurodevelopmental syndrome.

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Received Feb. 23, 2009; revised April 30, 2009; accepted May 28, 2009.

Correspondence should be addressed to Dr. Jeffrey L. Noebels, Department of Neurology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Email: jnoebels{at}bcm.edu

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