Epilepsy and intellectual disability (ID), including autism are often comorbid with one another in early life. Early postnatal development is characterized by a critical period (CP) of enhanced synaptic plasticity and learning. If epilepsy and seizures occur in the setting of rapid synaptic development, as is the case during the CP, there is the potential for excessive induction of activity dependent synaptic modification (plasticity) as well as disruption of the normal excitatory:inhibitory balance unique to this age window, and this in turn could affect brain development and neurobehavior. The central hypothesis of this proposal is that early life seizures can alter synaptogenesis and network plasticity, thereby disrupting aspects of the subsequent CP. To date, the limited evidence for an effect of seizure on CP events has been at the level of cellular and molecular changes, but has not been addressed quantitatively in vivo at a systems level. We will assess auditory cortical CP resulting from in vivo tone rearing in animals exposed to early life seizures (Aim 1). Next, we wil examine how the maturation of inhibition (Aim 2) and excitation (Aim 3) in specific auditory cortical networks contribute to the CP and how this is altered by early life seizures. Finally, we will perform pilot proof-of-principle experiments to test how seizure induced disruption of auditory CP correlates with seizure-induced neurobehavioral deficits, as well as whether seizure control in 2 mouse models of autism syndromes. If successful, these experiments will reveal new therapeutic targets for the treatment of ID and autism that accompany early life seizures.

Public Health Relevance

Epilepsy is the third most common major neurologic disease, and infancy and childhood are windows of higher incidence. Almost half of all epilepsy patients suffer some sort of cognitive and psychiatric disorders, and the incidence of cognitive problems including autism is high in children with epilepsy. Likewise, there is a higher incidence of epilepsy in autism and other intellectual developmental disorders. Here we evaluate whether epilepsy can affect the normal processes of early brain development, and whether there are molecular targets for intervention and treatment to reverse these changes. This grant application addresses several components of the Epilepsy Research Benchmarks (http://www.ninds.nih.gov/research/epilepsyweb/2007_benchmarks.htm ) Benchmarks Area III: Prevent, limit, and reverse the co-morbidities associated with epilepsy and its treatment. B. Identify predictors and underlying mechanisms that contribute to co-morbidities. C. Determine the optimal treatments for the neuropsychiatric and cognitive comorbidities in people with epilepsy. D. Prevent or limit other adverse consequences occurring in people with epilepsy.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Whittemore, Vicky R
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University of Pennsylvania
Schools of Medicine
United States
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Lippman-Bell, Jocelyn J; Zhou, Chengwen; Sun, Hongyu et al. (2016) Early-life seizures alter synaptic calcium-permeable AMPA receptor function and plasticity. Mol Cell Neurosci 76:11-20
Simonato, Michele; Brooks-Kayal, Amy R; Engel Jr, Jerome et al. (2014) The challenge and promise of anti-epileptic therapy development in animal models. Lancet Neurol 13:949-60
Fernández, Iván Sánchez; Chapman, Kevin E; Peters, Jurriaan M et al. (2013) The tower of Babel: survey on concepts and terminology in electrical status epilepticus in sleep and continuous spikes and waves during sleep in North America. Epilepsia 54:741-50