Objective Impairment in consciousness is a debilitating symptom during and after seizures; however, its mechanism remains unclear. Limbic seizures have been shown to spread to arousal circuitry to result in a "network inhibition" phenomenon. However, prior animal model studies did not relate physiological network changes to behavioral responses during or following seizures. Methods Focal onset limbic seizures were induced while rats were performing an operant conditioned behavioral task requiring response to an auditory stimulus to quantify how and when impairment of behavioral response occurs. Correct responses were rewarded with sucrose. Cortical and hippocampal electrophysiology measured by local field potential recordings was analyzed for changes in low‐ and high‐frequency power in relation to behavioral responsiveness during seizures. Results As seen in patients with seizures, ictal (p < .0001) and postictal (p = .0015) responsiveness was variably impaired. Analysis of cortical and hippocampal electrophysiology revealed that ictal (p = .002) and postictal (p = .009) frontal cortical low‐frequency 3–6‐Hz power was associated with poor behavioral performance. In contrast, the hippocampus showed increased power over a wide frequency range during seizures, and suppression postictally, neither of which were related to behavioral impairment. Significance These findings support prior human studies of temporal lobe epilepsy as well as anesthetized animal models suggesting that focal limbic seizures depress consciousness through remote network effects on the cortex, rather than through local hippocampal involvement. By identifying the cortical physiological changes associated with impaired arousal and responsiveness in focal seizures, these results may help guide future therapies to restore ictal and postictal consciousness, improving quality of life for people with epilepsy.

Amyloid deposits in Alzheimer's disease (AD) are surrounded by large numbers of plaque-associated axonal spheroids (PAAS). PAAS disrupt axonal electrical conduction and neuronal network function, and correlate with AD severity. However, the mechanisms that govern their formation remain unknown. To uncover the molecular architecture of PAAS, we applied proximity labeling proteomics of spheroids in human AD postmortem brains and mice. We then implemented a human iPSC-derived AD model recapitulating PAAS pathology for mechanistic studies. Using this strategy, we uncovered hundreds of previously unknown PAAS-enriched proteins and signaling pathways, including PI3K/AKT/mTOR. Phosphorylated mTOR was highly enriched in PAAS and strongly correlated with disease severity in humans. Importantly, pharmacological mTOR inhibition in iPSC-derived human neurons or AAV-mediated knockdown in mice, led to a marked reduction of PAAS pathology. Altogether, our study provides a novel platform to examine mechanisms of axonal pathology in neurodegeneration and to evaluate the therapeutic potential of novel targets.