Persistent Suppression of Phrenic Motor Plasticity after Mild Acute Systemic Inflammation in Adult Rats

Inflammation, which is commonly associated with lung and neurological disorders, undermines a form of spinal serotonin-dependent respiratory motor plasticity elicited by moderate acute intermittent hypoxia (mAIH), known as phrenic long-term facilitation (pLTF). In adult rats, pLTF suppression has been studied 24 hours following exposure to low-dose lipopolysaccharide (LPS) or 8 hours of intermittent hypoxia simulating sleep apnea. In this timeframe, pLTF is suppressed by an adenosine 2A (A 2A ) receptor and p38 MAP kinase-dependent mechanism. However, the duration of plasticity suppression following acute inflammation is unknown. We hypothesized that pLTF recovers when neuroinflammatory molecules return to normal. Thus, in Sprague Dawley rats, we assessed pLTF, ventral spinal (C3-C6) adenosine, and pro-inflammatory molecules post-LPS (100 μg/kg i.p.). LPS increased spinal adenosine and microglial inflammatory genes at 24 hours, but not 1-week post-LPS. Regardless, mAIH-induced pLTF remained suppressed for 3 weeks, and then slowly recovered between 3 to 5 weeks post-LPS. Thus, pLTF suppression outlasts active inflammation. Contrary to 24 hours, at 1-week post-LPS, spinal A2A receptor inhibition (MSX-3) failed to restore pLTF, while spinal p38 MAPK inhibition (SB202190) rescued pLTF at both 24 hours and 1-week post-LPS. These findings suggest that distinct mechanisms underlie pLTF suppression at 24 hrs vs 1-week post-LPS, although both mechanisms share downstream p38 MAPK signaling. Since mAIH is emerging as a therapeutic modality to improve respiratory and non-respiratory motor function in people with neurological disorders, targeting p38 MAPK may prevent persistent plasticity suppression in individuals with a history of inflammation.