Tracking the evolution of synaptic dysplasticity after early life seizures

PROJECT SUMMARY Multiple lines of clinical and experimental evidence suggest that seizures in early life can be associated with long lasting cognitive and behavioral deficits. In rodent models, we have showed that early life seizures (ELS) impair normal synaptic plasticity, critical period plasticity, later life learning and social behavioral deficits. Improved understanding as to how seizure activity and hyperexcitable networks dysregulate synaptic plasticity will be required to develop new therapeutic strategies in this clinical space where no current cure exists. We will focus on dysplasticity related to alterations of the excitatory synaptic glutamate receptor and its related signaling pathways. Tracking alterations of synaptic glutamate receptors in neurons activated by ELS is a specific challenge given that they occur in the midst of the synaptic critical period, the refinement of synaptic connections and the dispersion of neurons with development, which makes it difficult to localize neurons for functional studies later in life, despite the persistence of impaired synaptic plasticity and cognitive deficits. Similarly, sampling of a neuronal population for gene and protein expression may fail to show alterations occurring in a small, critical, subset of cells. To address these issues, we have adapted a method to permanently label cells activated by ELS in mice so that we can measure synaptic responses, gene and protein expression at a single neuron level, and then differentially label them during subsequent later life seizure (LLS) events. Using our ELS models, we aim to determine whether neurons activated by ELS have persistent, life-long, alterations of glutamate receptor function associated with impaired synaptic plasticity and hyperexcitability compared to neurons from no-seizure control mice (Aim 1). We will correlate these functional changes with measurements of gene and protein expression related to glutamate receptor function compared to neurons from no-seizure control mice (Aim 2). Finally, we will determine whether neurons activated by ELS are differentially affected by a second later life seizure (LLS) in adulthood compared to control neurons in seizure free mice (Aim 3). The synapse is a convergence point for the likely many upstream derangements of network function, and therefore an ideal target of study. We hypothesize that tracking the evolution of changes over time in select neuronal populations following ELS will allow us to both “stage” the evolution of changes and identify new therapeutic targets for this comorbidity and consequence of seizures in the immature brain.