Synaptic activity-independent persistent plasticity in endogenously active mammalian motoneurons

Potentiation and depression of glutamate receptor function in hippocampal, cerebellar, and cortical neurons are examples of persistent changes in synaptic function that underlie important behavioral adaptations such as learning and memory. Persistent changes in synaptic function relevant for motor behaviors have not been demonstrated in mammalian motoneurons. We demonstrate that adaptive changes in (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrobromide (AMPA) receptor function at endogenously active synapses occur in motoneurons in neonatal rodents. We found a form of serotonin (5-HT)-dependent synaptic plasticity in hypoglossal (XII) motoneurons, which control tongue muscles affecting upper airway function, that is metamodulated by metabotropic glutamate receptors. Episodic, but not continuous, activation of postsynaptic 5-HT type 2 (5-HT2) receptors on hypoglossal (XII) motoneurons leads to long-lasting increases in their AMPA receptor-mediated respiratory drive currents and associated XII nerve motor output. Antagonism of group-I metabotropic glutamate receptors blocks induction of the 5-HT-induced increase in excitability. We propose that this activity-independent postsynaptic 5-HT-mediated plasticity represents the cellular mechanism underlying long-term facilitation, i.e., persistent increases in respiratory motor output and ventilation seen in humans and rodents in response to episodic hypoxia. Loss of activity in XII motoneurons is common during sleep causing snoring and, in serious cases, airway obstruction that interrupts breathing, a condition known as obstructive sleep apnea. These results may provide the basis for rationale development of therapeutics for obstructive sleep apnea in humans.