While central autonomic cardiorespiratory dysfunction underlies sudden unexpected death in epilepsy (SUDEP), the specific neural mechanisms that lead to SUDEP remain to be determined. Here we took an advantage of single cell neuronal Ca2+ imaging and intrahippocampal kainic acid (KA)-induced chronic epilepsy in mice to investigate progressive changes in key cardiorespiratory brainstem circuits during chronic epilepsy. Following induction of status epilepticus (SE), we observed that the adaptive

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... ventilatory responses to hypercapnia were reduced in mice with chronic epilepsy for 5 weeks post-SE. These changes were paralleled by reduced chemosensitivity of neurons in the retrotrapezoid nucleus (RTN), an important centre for respiratory chemosensitivity. Over the same period, chemosensory responses of the presympathetic RVLM neurons showed a slower decrease. Mice with chronic epilepsy were more sensitive to chemoconvulsants and exhibited a greatly reduced latency to seizure induction compared to naive mice. This enhanced sensitivity to seizures, which invade the RTN, puts the chemosensory circuits at further risk and increases the chances of terminal apnoea. Our findings establish a dysfunctional breathing phenotype with its RTN neuronal correlate in mice with chronic epilepsy and suggests a functional non-invasive biomarker test, based on respiratory chemosensitivity, to identify people with epilepsy at risk of SUDEP.