Pediatric seizures: role of IP3R Ca2+ release channels

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Alcohol withdrawal following prenatal alcohol exposure (PAE) is frequently associated with generalized tonic- clonic seizures (GTCS) and epilepsy in infants and young children. Our long-term goal is to understand how Ca2+ signaling can be used to prevent and treat PAE-related seizures. We recently developed a rat model of GTCSs following alcohol withdrawal after PAE, in which increased GTCS prevalence was observed in P7-P28 and P7- P35 female and male postpartum rats, respectively. In this model, neonate inferior colliculus (IC) neurons exhibit: i) increased Ca2+-dependent firing in postnatal stage and ii) increased Ca2+ release from inositol triphosphate receptor (IP3R) Ca2+ pools is increased in the IC in both pre-and postnatal stages. The experiments proposed here are designed to determine the precise contribution of three IP3R subtypes—IP3R1, IP3R2 and IP3R3 to GTCS susceptibility following alcohol withdrawal after a single PAE episode during the 2nd trimester, proving specific targets for developing new specific approaches. Our objective in this proposal is to investigate the role of Ca2+ release from intracellular IP3R Ca2+ pools in IC neuronal hyperexcitability in response to alcohol withdrawal after PAE in the 2nd trimester of gestation. Our working hypothesis is that alcohol withdrawal following PAE during the 2nd trimester PAE upregulates IP3R Ca2+ pools resulting in elevated Ca2+ release, which in turn contribute to IC neuronal hyperexcitability and increased seizure susceptibility. To test our central hypothesis, our experiments will combine Ca2+ imaging with electrophysiology, molecular genetics, and pharmacology. The research proposal seeks to address four questions: i) how does Ca2+ release from intracellular IP3R Ca2+ pools is altered in IC neurons of postpartum P35 female and male rats? ii) how does inhibition of Ca2+ release from IP3R Ca2+ pools suppressed IC neuronal firing in postpartum P35 female and rats prenatally exposed to alcohol at E18? iii) how does alcohol withdrawal following PAE alter IP3R mRNA and protein expression in the IC of postpartum PAE P35 female and male postpartum rats? and iv) how does inhibition of IP3R in the IC suppresses GTCS in postpartum PAE P28 and P35, respectively. Overall Impact: Other than generic anticonvulsant medication, there is no specific therapy for pediatric seizures related to alcohol withdrawal after PAE. By revealing how aberrant IP3R-gated Ca2+ release mechanisms contribute to pediatric seizures following alcohol withdrawal after PAE, we will increase understanding of these channels as potential therapeutic targets for managing PAE-related seizures.