AIH-induced respiratory plasticity and stem cell therapy have complementary translational potential to treat breathing deficits in patients with ALS.

In vitro long-term facilitation (ivLTF) is a novel form of activity-independent postsynaptic enhancement of AMPA receptor function in hypoglossal (XII) motoneurons that can be induced by intermittent activation of 5-HT 2 receptors. In vivo respiratory long-term facilitation (LTF) is characterized by a persistent 5-HT 2 receptor-dependent increase in respiratory motor output or ventilation after episodic exposures to hypoxia in adult rats. Here, we demonstrate that ivLTF can also be induced by episodic but not continuous stimulation of ␣1-adrenergic receptors that requires protein kinase C (PKC), but not PKA (protein kinase A), activation. Additionally, we show that in vivo respiratory LTF is also ␣1-adrenergic receptor dependent. We suggest that, in vivo, concurrent episodic activation of 5-HT 2 and ␣1-adrenergic receptors is necessary to produce long-lasting changes in the excitability of respiratory motoneurons, possibly involving PKC activation via the G␣ q -PLC (phospholipase C) signaling pathway common to both receptor subtypes. Such plasticity of XII motor output may increase upper airway muscle (innervated by XII nerve) tone and improve the likelihood that airway patency will be maintained. Elucidating the mechanism underlying LTF can be of clinical importance to the patients suffering from sleep-disordered breathing.

Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease. ALS selectively causes degeneration in upper and lower (spinal) motor neurons, leading to muscle weakness, paralysis and death by ventilatory failure. Although ventilatory failure is generally the cause of death in ALS, little is known concerning the impact of this disorder on respiratory motor neurons, the consequences of respiratory motor neuron cell death, or the ability of the respiratory control system to “fight back” via mechanisms of compensatory respiratory plasticity. Here we review known effects of ALS on breathing, including possible effects on rhythm generation, respiratory motor neurons, and their target organs: the respiratory muscles. We consider evidence for spontaneous compensatory plasticity, preserving breathing well into disease progression despite dramatic loss of spinal respiratory motor neurons. Finally, we review current and potential therapeutic approaches directed toward preserving the capacity to breathe in ALS patients.

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In rodent models of ALS (SOD1G93A rat), ventilation is maintained until late in disease progression, despite a paucity of surviving respiratory motor neurons. Thus, surviving motor neurons compensate for motor neuron loss and preserve ventilation. We tested the hypothesis that 5‐HT is necessary for such compensatory plasticity by measuring ventilatory capacity following 5‐HT depletion near disease end stage in SOD1G93A rats. When SOD1G93A rats decreased body mass 15%, mutants (and wild type litter mates) were given para‐chlorophenylalanine (PCPA; 300 mg/kg IP) or vehicle injections (0.9% NaCl, 7.5 ml/kg IP) for 2 days. Ventilatory measurements were made during baseline, hypoxic (10.5% O2), hypercapnic (7% CO2) and hypoxic/hypercapnic (10.5% O2/7% CO2) conditions via whole‐body plethysmography (n=3‐5 per group). PCPA had no effect (or actually increased) minute ventilation and tidal volume in all conditions studied in both mutant and wild type rats. PCPA decreased breathing frequency (f) in wild type rats; although f was lower in untreated mutant rats (vs wild type), PCPA had no additional effect. Our data provide no evidence that 5‐HT depletion impairs the capacity to increase ventilation in end‐stage SOD1G93A rats. However, we cannot rule out a role for 5‐HT in the induction (vs maintenance) of compensatory plasticity in SOD1G93A rats.[Supported by NIH NSO57778.]