Dysregulated Galanin Chemoreflex in Epilepsy: Implications for SUDEP

Central apnea driven by impaired CO₂ sensing is thought to contribute to sudden unexpected death in epilepsy (SUDEP). We tested whether chronic epilepsy alters the hypercapnic ventilatory response and the activity of galanin-expressing chemoreceptor neurons in the retrotrapezoid nucleus (RTN) and nucleus of the solitary tract (NTS). Five months after systemic kainic acid (KA) or saline, Wistar rats with spontaneous tonic-clonic seizures or controls were exposed for 1 h to 10% CO₂ or room air. Breathing frequency (fB) and heart rate (HR) were recorded with photoplethysmography; brainstems were processed by in situ hybridization for preprogalanin and immunohistochemistry for c-Fos (neuronal activation) with tyrosine hydroxylase (TH) and Phox2b (chemoreceptor neurons). KA rats showed a markedly blunted physiological response to CO₂ (ΔfB, p<0.01; ΔHR, p<0.0001) relative to controls. Baseline c-Fos in galaninergic RTN neurons was almost three-fold higher in epileptic animals (32.6 ± 5% vs 11.2 ± 2%) and rose to 59.2 ± 6% after hypercapnia (controls 33.9 ± 5%). In the NTS, CO₂ activated 15.7 ± 2% of preprogalanin neurons in KA rats versus 10.2 ± 2% in controls; baseline activation was also elevated (4.7 ± 1% vs 1.7 ± 0.5%). Thus, despite a hyper-responsive galaninergic chemoreceptor phenotype, ventilatory output is diminished. Our data suggest two, non-exclusive explanations: (1) chemoreceptor activity is up-regulated to compensate for suppressed downstream respiratory circuits; (2) galanin itself inhibits respiratory drive, masking the enhanced neuronal activation. Maladaptive plasticity within brainstem CO₂-sensing networks may therefore underlie respiratory failure and increased SUDEP risk in chronic epilepsy.