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

Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 08/2009; 29(27):8752-63. DOI: 10.1523/JNEUROSCI.0915-09.2009
Source: PubMed


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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    • "Analyses using genetically modified mouse models have been performed to explore the impact different ARX mutations have on neuronal development and cognitive functionality; these models demonstrate a similar genotype-phenotype correlation to humans [13]. Specifically, mouse models with an expansion mutation of the first polyalanine tract of Arx reveal that only tangential migration of GABA-ergic interneurons is lost, with no significant impact to radial migration [14], [15]. Thus, it appears that expansion of the first polyalanine tract of Arx results in context-specific defects in neural development. "
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    ABSTRACT: ARX/Arx is a homeodomain-containing transcription factor necessary for the specification and early maintenance of pancreatic endocrine α-cells. Many transcription factors important to pancreas development, including ARX/Arx, are also crucial for proper brain development. Although null mutations of ARX in human patients result in the severe neurologic syndrome XLAG (X-linked lissencephaly associated with abnormal genitalia), the most common mutation is the expansion of the first polyalanine tract of ARX, which results primarily in the clinical syndrome ISSX (infantile spasms). Mouse models of XLAG, ISSX and other human ARX mutations demonstrate a direct genotype-phenotype correlation in ARX-related neurologic disorders. Furthermore, mouse models utilizing a polyalanine tract expansion mutation have illustrated critical developmental differences between null mutations and expansion mutations in the brain, revealing context-specific defects. Although Arx is known to be required for the specification and early maintenance of pancreatic glucagon-producing α-cells, the consequences of the Arx polyalanine expansion on pancreas development remain unknown. Here we report that mice with an expansion mutation in the first polyalanine tract of Arx exhibit impaired α-cell specification and maintenance, with gradual α-cell loss due to apoptosis. This is in contrast to the re-specification of α-cells into β- and δ-cells that occurs in mice null for Arx. Overall, our analysis of an Arx polyalanine expansion mutation on pancreatic development suggests that impaired α-cell function might also occur in ISSX patients.
    PLoS ONE 11/2013; 8(11):e78741. DOI:10.1371/journal.pone.0078741 · 3.23 Impact Factor
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    • "Histologically, cortex from these mice shows a 1/3 reduction of GABAergic interneurons staining for calbindin, and preservation of parvalbumin and NPY containing interneurons. Within striatum, on the other hand, there is a reduction NPY and cholinergic interneurons (Price et al., 2009). "
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    ABSTRACT: The application of metabolic imaging and genetic analysis, and now the development of appropriate animal models, has generated critical insights into the pathogenesis of epileptic encephalopathies. In this article we present ideas intended to move from the lesions associated with epileptic encephalopathies toward understanding the effects of these lesions on the functioning of the brain, specifically of the cortex. We argue that the effects of focal lesions may be magnified through the interaction between cortical and subcortical structures, and that disruption of subcortical arousal centers that regulate cortex early in life may lead to alterations of intracortical synapses that affect a critical period of cognitive development. Impairment of interneuronal function globally through the action of a genetic lesion similarly causes widespread cortical dysfunction manifesting as increased delta slow waves on electroencephalography (EEG) and as developmental delay or arrest clinically. Finally, prolonged focal epileptic activity during sleep (as occurring in the syndrome of continuous spike-wave in slow sleep, or CSWSS) might interfere with local slow wave activity at the site of the epileptic focus, thereby impairing the neural processes and, possibly, the local plastic changes associated with learning and other cognitive functions. Seizures may certainly add to these pathologic processes, but they are likely not necessary for the development of the cognitive pathology. Nevertheless, although seizures may be either a consequence or symptom of the underlying lesion, their effective treatment can improve outcomes as both clinical and experimental studies may suggest. Understanding their substrates may lead to novel, effective treatments for all aspects of the epileptic encephalopathy phenotype.
    Epilepsia 11/2013; 54 Suppl 8(s8):6-13. DOI:10.1111/epi.12417 · 4.57 Impact Factor
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    • "No difference was seen when heterozygous animals and wildtype animals were paired, suggesting that the Ala56 allele only has a significant effect on this phenotype in the homozygous state. From published data, the tube test appears to be a very sensitive test of altered social function in genetic mouse models related to ASD, with significant findings in the Fragile X syndrome model [44], the Rett syndrome model [45], the Arx((GCG)10+7) infantile spasms model [46], the Potocki-Lupski model Dp(11)/17/+ mice [47], and the Dhcr7 heterozygous model of Smith-Lemli-Opitz Syndrome [48]. On the other hand, the tube test may also reveal significant differences in mice with altered motor function or impulsivity, or under conditions of social stress [49], and was originally developed as a test of social hierarchy/dominance, making it a sensitive but not specific test for ASD-relevant social behavior. "
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    ABSTRACT: Previously, we identified multiple, rare serotonin (5-HT) transporter (SERT) variants in children with autism spectrum disorder (ASD). Although in our study the SERT Ala56 variant was over-transmitted to ASD probands, it was also seen in some unaffected individuals, suggesting that associated ASD risk is influenced by the epistatic effects of other genetic variation. Subsequently, we established that mice expressing the SERT Ala56 variant on a 129S6/S4 genetic background display multiple biochemical, physiological and behavioral changes, including hyperserotonemia, altered 5-HT receptor sensitivity, and altered social, communication, and repetitive behavior. Here we explore the effects of genetic background on SERT Ala56 knock-in phenotypes. To explore the effects of genetic background, we backcrossed SERT Ala56 mice on the 129 background into a C57BL/6 (B6) background to achieve congenic B6 SERT Ala56 mice, and assessed autism-relevant behavior, including sociability, ultrasonic vocalizations, and repetitive behavior in the home cage, as well as serotonergic phenotypes, including whole blood serotonin levels and serotonin receptor sensitivity. One consistent phenotype between the two strains was performance in the tube test for dominance, where mutant mice displayed a greater tendency to withdraw from a social encounter in a narrow tube as compared to wildtype littermate controls. On the B6 background, mutant pup ultrasonic vocalizations were significantly increased, in contrast to decreased vocalizations seen previously on the 129 background. Several phenotypes seen on the 129 background were reduced or absent when the mutation was placed on the B6 background, including hyperserotonemia, 5-HT receptor hypersensivity, and repetitive behavior. Our findings provide a cogent example of how epistatic interactions can modulate the impact of functional genetic variation and suggest that some aspects of social behavior may be especially sensitive to changes in SERT function. Finally, these results provide a platform for the identification of genes that may modulate the risk of ASD in humans.
    Molecular Autism 10/2013; 4(1):35. DOI:10.1186/2040-2392-4-35 · 5.41 Impact Factor
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