Development of aberrant cortical interneuron circuitry in genetic mouse models of absence epilepsy

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Abstract Epilepsy affects over 2 million of people in the United States, causing significant morbidity with a high cost to society. While the behavioral and electrophysiological correlates of seizures in patients and animal models have been studied for over a century, the underlying circuit abnormalities are still being elucidated. Generalized spike-wave (SW) absence sei- zures are the most common seizure disorder in children and thought to be exclusively of genetic origin. While over 20 genes are discovered and studied in SW epilepsies, it is still unclear how each genetic lesion impairs normal circuit devel- opment and ultimately results in a seizure-prone cortical circuit. Since the SW seizure phenotype can be very similar de- spite disparate genetic etiologies, a stereotypical circuit deficit may exist which underlies the expression of this seizure pattern. More recently, as we have begun to understand the wiring principles of cortical microcircuits at the level of cell types, it has become possible to ask how disruption of these canonical networks may be responsible for initiating seizure activity and impairing cognitive functions in SW epilepsies, whether the pathogenic circuit changes overlap despite dis- parate molecular lesions, and how a seizure-prone circuit emerges from inherited molecular defects to favor seizure on- set at predictable developmental time-points. This information not only suggests novel and broadly-applicable therapeu- tic targets, but also leads to valuable insights into the functional roles of distinct cell types and specific connectivity principles in normal brain. To answer these important questions, we are taking advantage of three mouse models of ab- sence epilepsy, stargazer, tottering and Gabrg2 mutant mice, which harbor mutations in three unrelated genes but share the same SW phenotype, and propose a comprehensive microcircuit comparison among distinct genotypes at the level of cell types and their connections. We perform a large-scale circuit analysis across a whole column of the somatosen- sory cortex (S1) in three models along the seizure development, by leveraging a high-throughput multi-patching method (up to 12-patch) we recently developed. We will measure multiple neuronal features of distinct cell types within the S1 epileptic circuit, with an emphasis on connectivity and morphology of major groups of cortical GABAergic interneurons. In parallel, the same analysis will be performed on WT littermates as controls to reveal cell type-specific connectivity changes as a function of the genotype and developmental stage. These comprehensive, dynamic comparisons, based on large-scale circuit analyses with sensitive, state-of-the-art methods, will reveal the full extent of abnormal microcircuit structure and functions that are closely associated with seizure onset. Our preliminary data uncover several connectivity defects in these models. The most striking is that stereotypical connectivity and morphology of somatostatin-expressing Martinotti cells are severely disrupted, and this disruption appears to emerge only after seizure onset and is shared by models, suggesting a common circuit deficit underlying absence epilepsy. The potential causative circuit mechanisms will be further tested via network modeling and an in vivo chemogenetic assay. Identification of causative circuit deficits gen- eralized across genetically heterogeneous, yet highly stereotyped SW seizures will direct the field toward the develop- ment of innovative, broadly applicable circuit-based interventions for absence epilepsy and its related comorbidities.