Ampakine CX717 potentiates intermittent hypoxia-induced hypoglossal long-term facilitation.
Glutamatergic currents play a fundamental role in regulating respiratory motor output and are partially mediated by α-amino-3-hydroxy-5-methyl-isoxazole-propionic acid (AMPA) receptors throughout the premotor and motor respiratory circuitry. Ampakines are pharmacological compounds that enhance glutamatergic transmission by altering AMPA receptor channel kinetics. Here, we examined if ampakines alter the expression of respiratory long-term facilitation (LTF), a form of neuroplasticity manifested as a persistent increase in inspiratory activity following brief periods of reduced O2 [intermittent hypoxia (IH)]. Current synaptic models indicate enhanced effectiveness of glutamatergic synapses after IH, and we hypothesized that ampakine pretreatment would potentiate IH-induced LTF of respiratory activity. Inspiratory bursting was recorded from the hypoglossal nerve of anesthetized and mechanically ventilated mice. During baseline (BL) recording conditions, burst amplitude was stable for at least 90 min (98 ± 5% BL). Exposure to IH (3 × 1 min, 15% O2) resulted in a sustained increase in burst amplitude (218 ± 44% BL at 90 min following final bout of hypoxia). Mice given an intraperitoneal injection of ampakine CX717 (15 mg/kg) 10 min before IH showed enhanced LTF (500 ± 110% BL at 90 min). Post hoc analyses indicated that CX717 potentiated LTF only when initial baseline burst amplitude was low. We conclude that under appropriate conditions ampakine pretreatment can potentiate IH-induced respiratory LTF. These data suggest that ampakines may have therapeutic value in the context of hypoxia-based neurorehabilitation strategies, particularly in disorders with blunted respiratory motor output such as spinal cord injury.
Department of Physical Therapy, College of Public Health and Health Professions, University of Florida, Gainesville, Florida; McKnight Brain Institute, University of Florida, Gainesville, Florida; and Center for Respiratory Research and Rehabilitation, University of Florida, Gainesville, Florida.
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SM
Turner
Department of Pediatrics, Division of Pulmonary Medicine, College of Medicine, University of Florida, Gainesville, Florida;
M K
MK
ElMallah
Department of Physical Therapy, College of Public Health and Health Professions, University of Florida, Gainesville, Florida;
A K
AK
Hoyt
Department of Physiology, University of Alberta, Edmonton, Canada;
J J
JJ
Greer
Department of Physical Therapy, College of Public Health and Health Professions, University of Florida, Gainesville, Florida; McKnight Brain Institute, University of Florida, Gainesville, Florida; and Center for Respiratory Research and Rehabilitation, University of Florida, Gainesville, Florida ddf@phhp.ufl.edu.
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DD
Fuller
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D007002:Hypoglossal Nerve / Q000187:drug effects* / Q000503:physiopathology; D000860:Hypoxia / Q000503:physiopathology*; D007555:Isoxazoles / Q000494:pharmacology*; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D008297:Male; D057507:Mice, 129 Strain; D023421:Models, Animal; D000066530:Neurological Rehabilitation; D018373:Peripheral Nervous System Agents / Q000494:pharmacology*; D012119:Respiration; D012121:Respiration, Artificial
C542518:CX717; D007555:Isoxazoles; D018373:Peripheral Nervous System Agents
AMPA; mouse; plasticity; respiratory