The early epileptic encephalopathies are a group of syndromes characterized by intractable seizures, poor developmental outcome, and onset before six years of age. As a child neurologist specializing in pediatric epilepsy, I spend much of my clinical time counseling families whose children have these conditions. I find the conversations to be frustrating as I inform the families that our treatments are not designed for these diseases and little basic research exists to guide diagnosis and treatment. There is a pressing need for further research into the early intractable epilepsies. Developing models to study these syndromes is essential if advances in diagnosis and treatment are to be made. Recently, mutations in the aristaless-related homeobox gene (ARX), a developmental transcription factor, have been shown to cause X-linked infantile spasms syndrome and other early epileptic encephalopathies. Our experiments have shown that selective genetic deletion of Arx in interneurons (Arx CKO) results in abnormal migration of GABAergic interneurons, altered EEG activity, and spontaneous seizures. These data lead us to hypothesize that early loss of interneurons, in conditional Arx mice, alters the development of normal network function leading to intractable seizures and cognitive dysfunction modeling the early epileptic encephalopathies. This proposal both formulates experiments to examine the underlying pathophysiological processes of how interneuron dysfunction leads to seizures and encephalopathy as well as develops training opportunities to facilitate my transition to a career as an independent investigator. To study how Arx loss leads to seizures and mental retardation I first propose to determine the extent of circuit level dysfunction using a voltage sensitive dye imaging technique. Next, we will record and compare the development of control and Arx CKO mutant mice EEG and single unit activity during cortical and hippocampal rhythms to determine how rhythms are interrupted and which interneurons are involved. These studies will ascertain if interrupting interneuronal development alters the normal rhythms that bind cognitive processes. Finally, we will test the cognitive function of the mice, using a battery of behavioral techniques, to provide evidence linking circuit and network level dysfunction to the cognitive deficits of the mice. In addition to the proposed experiments, I have created a plan to help develop the skills needed for my transition to independence while working at the Children's Hospital of Philadelphia and the University of Pennsylvania. From these studies I will learn two techniques to implement in my future work. These studies will also set the foundation of a model to be used to understand how alterations in interneuronal development lead to an early epileptic encephalopathy.

Public Health Relevance

Many children are stricken with a severe form of epilepsy early in life and go on to develop medically refractory seizures and severe cognitive deficits. Recently, mutations in ARX, a protein believed to control how interneurons develop, have been linked to families with an X-linked pattern of seizures and mental retardation. Using behavioral, EEG, and physiological techniques we will determine how loss of ARX disrupts normal brain function and leads to seizures and mental retardation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02NS065975-03
Application #
8270485
Study Section
NST-2 Subcommittee (NST)
Program Officer
Whittemore, Vicky R
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$179,582
Indirect Cost
$13,302
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Simonet, Jacqueline C; Sunnen, C Nicole; Wu, Jue et al. (2015) Conditional Loss of Arx From the Developing Dorsal Telencephalon Results in Behavioral Phenotypes Resembling Mild Human ARX Mutations. Cereb Cortex 25:2939-50
Sunnen, C Nicole; Simonet, Jacqueline C; Marsh, Eric D et al. (2014) Arx is required for specification of the zona incerta and reticular nucleus of the thalamus. J Neuropathol Exp Neurol 73:253-61
Bourgeois, Elliot B; Johnson, Brian N; McCoy, Almedia J et al. (2014) A toolbox for spatiotemporal analysis of voltage-sensitive dye imaging data in brain slices. PLoS One 9:e108686
Falk, Marni J; Li, Dong; Gai, Xiaowu et al. (2014) AGC1 Deficiency Causes Infantile Epilepsy, Abnormal Myelination, and Reduced N-Acetylaspartate. JIMD Rep 14:77-85
Paciorkowski, Alex R; Traylor, Ryan N; Rosenfeld, Jill A et al. (2013) MEF2C Haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways. Neurogenetics 14:99-111
Mirzaa, Ghayda M; Paciorkowski, Alex R; Marsh, Eric D et al. (2013) CDKL5 and ARX mutations in males with early-onset epilepsy. Pediatr Neurol 48:367-77
Abend, Nicholas S; Gutierrez-Colina, Ana; Zhao, Huaqing et al. (2011) Interobserver reproducibility of electroencephalogram interpretation in critically ill children. J Clin Neurophysiol 28:15-9