Early life seizures disrupt critical period plasticity

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 will examine how the maturation of inhibition and excitation (Aim 2) in specific auditory cortical networks contribute to the CP and how this is altered by early life seizures. Finally, in Aim 3, we will perform pilot proof-of-principle experiments to test how seizure induced disruption of auditory CP correlates with seizure-induced neurobehavioral deficits, which we will attempt to rescue through seizure control in a mouse model of autism syndromes. If successful, these experiments will reveal new therapeutic targets for the treatment of ID and autism that accompany early life seizures.