UCSF

Temporal lobe epilepsy (TLE) is the most common focal epilepsy in adults and the form most often resistant to medication. Despite more than thirty antiseizure drugs, the majority of patients with TLE and hippocampal sclerosis continue to have seizures, and the only definitive options that remain are the surgical removal or ablation of the diseased brain. This dissertation asks whether a single protein within the reorganized hippocampal circuit can be removed to stop seizures while leaving the rest of brain function intact.The work centers on ATP8A1, a synaptic-vesicle–associated phospholipid flippase that is selectively required to sustain neurotransmitter release during high-frequency firing. In the intrahippocampal kainic acid (IHKA) mouse model of TLE, I show that ATP8A1 is not lost during disease but is redistributed into the aberrant mossy fiber sprouts of dentate granule cells, placing it within the very circuits that propagate seizures. Removing ATP8A1 constitutively abolishes chronic spontaneous seizures even though interictal spikes and hippocampal sclerosis persist. Whole-cell recordings show that this protection arises because ATP8A1 loss selectively prevents high-frequency vesicle mobilization at sprouted mossy fiber synapses while sparing low-frequency transmission, effectively uncoupling the structural pathology of TLE from its seizure output. Focal partial deletion of ATP8A1 within the hippocampal epileptic focus in chronically epileptic IHKA mice results in complete resolution of seizures with a >99% reduction in electrographic seizures. I further show that focal, adult-onset deletion restricted to the seizure focus not only stops seizures but rescues the cognitive and affective deficits of chronic epilepsy, in contrast to constitutive deletion through development, which carries its own baseline behavioral cost. Finally, in human TLE tissue, ATP8A1 shows the same regional enrichment and disease-associated reorganization observed in mouse, is transcriptionally enriched in granule cell populations by single-nucleus sequencing, and is recoverable from the synaptic fraction, establishing cross-species conservation. Together, these findings identify ATP8A1 as a molecular gatekeeper of seizure generalization and define selective disruption of high-frequency presynaptic transmission as a circuit-specific therapeutic strategy for drug-resistant TLE.