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

• DOI: 10.1523/jneurosci.0915-09.2009
• Publication Date: 2009-07-08T17:28:13Z
• Authors: M. G. Price; J. W. Yoo; D. L. Burgess; F. Deng; R. A. Hrachovy; J. D. Frost; J. L. Noebels
• Keywords: Interneuron; Forebrain

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