Infantile spasms are epileptic seizures that appear within a spectrum of infantile epileptic encephalopathies with poor prognosis. They are age-specific and have different mechanisms and pharmacosensitivity from other seizures. They have multiple etiologies, among which inflammatory processes have been implicated. An important feature of early brain development is the presence of depolarizing GABAA receptor signaling, needed for normal development, which gradually shifts to the normal hyperpolarizing GABAA receptor signaling seen in more mature ages. Using rat and mouse models of infantile spasms, we have found evidence that the presence of depolarizing GABAA receptor signaling in the setting of focal cortical inflammation, may underlie the age-specific susceptibility to inflammation-induced spasms and may predispose to a more severe phenotype. Here we investigate the interactions between depolarizing GABAA receptor signaling and inflammation that lead to age-specific expression of spasms and predispose to a more severe phenotype. We will also investigate whether this GABA inflammation interaction affects subsequent epilepsy in adulthood. We will use a combination of stereotactic surgeries, video-EEG monitoring, histology, gene and protein expression studies, in vitro electrophysiology, and drug administrations to determine the molecular and electrophysiological mechanisms involved and identify new candidate targets for novel treatments for infantile spasms. Our studies are expected to deliver new candidate targets for the development of new therapeutics for infantile spasms and subsequent epilepsies.
Infantile spasms are age-specific epileptic seizures that manifest within a spectrum of early life epileptic encephalopathies of infancy with poor prognosis. There is a need for better understanding of their mechanisms and identification of more effective, age-appropriate treatments. Our preliminary studies indicate that age- specific interactions between GABAA receptor signaling and inflammatory processes are important in defining the age-specific susceptibility to infantile spasms and their progression. In this proposal, we will test this hypothesis and will try to identify new molecular targets for more effective therapeutic interventions for infantile spasms and test if these mechanisms also influence the development of epilepsies that persist through adulthood.
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