Increased spinal adenosine impairs phrenic long-term facilitation in aging rats

Area of Science:

• Neuroscience
• Respiratory Physiology
• Aging Research

Background:

• Moderate acute intermittent hypoxia (mAIH) normally induces phrenic long-term facilitation (pLTF), a spinal respiratory motor plasticity.
• This plasticity is reduced in aged rats due to unknown mechanisms.
• In young adults, mAIH activates competing serotonin 2 and adenosine 2A (A2A) receptor pathways, with adenosine constraining plasticity.

Purpose of the Study:

• To investigate the hypothesis that elevated basal adenosine levels in aged rats undermine mAIH-induced pLTF.
• To determine if spinal A2A receptor inhibition can restore pLTF in aged rats.

Main Methods:

• Young (3-6 mo) and aged (20-22 mo) male rats received intrathecal A2A receptor antagonist (MSX-3) or vehicle.
• Rats were subjected to mAIH (3x5-min episodes; Po2=45-55 mmHg).
• Phrenic nerve activity was recorded to assess pLTF; spinal adenosine levels were measured.

Main Results:

• In young males, A2A inhibition enhanced pLTF (119%) vs. vehicle (55%).
• In aged males, basal pLTF was reduced (25%), but A2A inhibition significantly increased it (186%), exceeding young male levels.
• Basal spinal adenosine levels were 2-3 fold higher in aged vs. young males.

Conclusions:

• Elevated spinal adenosine in aged rats, via A2A receptor activation, actively suppresses mAIH-induced pLTF.
• Selective spinal A2A receptor inhibition effectively restores pLTF in aged rats.
• These findings highlight age-related changes in neuroplasticity mechanisms and suggest A2A antagonism as a strategy to enhance mAIH-based therapies for age-related movement disorders.