Inflammation modifies breathing phenotype in mice with epilepsy.

Impaired CO₂ responsiveness in epilepsy can result in hypoventilation and hypercapnia and these respiratory disturbances are key contributors to Sudden Unexpected Death in Epilepsy (SUDEP). While mild to moderate inflammation is known to modulate respiratory function, its specific role in regulating respiratory responses in the context of epilepsy remains unclear. We studied the effects of lipopolysaccharide (LPS)-induced inflammation and microglial inhibition via minocycline during the acute and chronic phases of epilepsy on hypercapnic ventilatory responses (HCVR) in the intrahippocampal kainic acid model of temporal lobe epilepsy in male C57BL/6 mice. LPS treatment during acute seizures and minocycline during spontaneous seizures in the chronic phase of epilepsy restored the impaired HCVR in mice. Notably, LPS treatment during acute seizures also reduced the frequency of spontaneous seizures. In contrast, minocycline given during acute seizures and LPS administered during chronic epilepsy further exacerbated HCVR impairment. Immunohistochemical analysis of chemosensitive retrotrapezoid nucleus (RTN) revealed varied effects of different treatments in epileptic mice on microglia density, morphology and their expression of triggering receptor expressed on myeloid cells 2 (TREM2), P2Y12 receptor, and astrocytic adenosine 2A receptor (A2AR). Overall, the inflammation during epileptogenic or acute phase preserves HCVR and reduces spontaneous seizure frequency in chronic epilepsy, whereas in chronic phase it worsens HCVR. Although not yet fully validated, changes in microglial and astrocytic receptor expression could contribute to this HCVR impairment and may represent a mechanistic target for preserving HCVR in epilepsy; a dysfunction that could potentially lead to SUDEP.