Altered PI3K/mTOR signaling within the forebrain leads to respiratory deficits in a mouse model of epilepsy

People with epilepsy may experience sudden death due to respiratory failure through mechanisms that are currently not well understood. Epilepsy causing mutations are thought to elicit seizures due to altered function of forebrain circuits, yet breathing is controlled largely by the brainstem. To investigate how altered forebrain activity could impact breathing, we examined respiratory and seizure phenotypes in a mouse epilepsy model with a forebrain–specific deletion of the phosphatase and tensin homolog (PTEN) gene (PTEN–cKO). Using chronic diaphragm electromyography (EMG) and cortical electroencephalography (EEG), we monitored PTEN–cKO mice (6 males and 4 females) and control littermates (6 males and 3 females) continuously from pre–seizure onset through end–stage disease. PTEN–cKO mice develop spontaneous seizures that progress in frequency with age, accompanied by gradual changes in respiratory function, even during interictal periods. As seizure burden increases, PTEN-cKO mice experience an increased frequency of interictal apneas, slowing of respiratory rhythm, prolongation of inspiratory bursts, and elevation of inspiratory effort. All animals experienced a terminal apnea prior to cardiac arrest. These findings demonstrate that PTEN deletion in the forebrain disrupts the control of breathing and leads to terminal respiratory failure. Significance Statement Epilepsy typically alters forebrain function, but whether this alone is sufficient to alter the control of breathing, particularly in the absence of seizures, remains unclear. Here, we show in a spontaneous seizure model that forebrain-specific mutation of PTEN leads to progressive respiratory abnormalities initially manifesting as increased interictal apneas, then progressing to slower, deeper breathing and ultimately terminating in respiratory failure. These findings suggest that forebrain circuit dysfunction in epilepsy can disrupt respiratory control, potentially increasing the risk of sudden unexpected death in epilepsy (SUDEP).