Neural correlate of reduced respiratory chemosensitivity during chronic epilepsy

Central autonomic cardiorespiratory dysfunction underlies sudden unexpected death in epilepsy (SUDEP). Here we used single cell neuronal Ca 2+ 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), adaptive ventilatory responses to hypercapnia were reduced in mice with chronic epilepsy for 5 weeks post-SE with partial recovery at week 7. These changes were paralleled by post-SE alterations in the chemosensory responses of neurons in the retrotrapezoid nucleus (RTN). Neurons that displayed adapting responses to hypercapnia were less prevalent and exhibited smaller responses over weeks 3-5, whereas neurons that displayed graded responses to hypercapnia became more prevalent by week 7. Over the same period, chemosensory responses of the presympathetic rostral ventrolateral medullary neurons showed no change. Mice with chronic epilepsy showed enhanced sensitivity to seizures, which can invade the RTN and possibly impair further the chemosensory circuits. Our work suggests that assessment of respiratory chemosensitivity may have potential for identifying people at risk of SUDEP.