Ammonia triggers neuronal disinhibition and seizures by impairing astrocyte potassium buffering.
Ammonia is a ubiquitous waste product of protein metabolism that can accumulate in numerous metabolic disorders, causing neurological dysfunction ranging from cognitive impairment to tremor, ataxia, seizures, coma and death. The brain is especially vulnerable to ammonia as it readily crosses the blood-brain barrier in its gaseous form, NH3, and rapidly saturates its principal removal pathway located in astrocytes. Thus, we wanted to determine how astrocytes contribute to the initial deterioration of neurological functions characteristic of hyperammonemia in vivo. Using a combination of two-photon imaging and electrophysiology in awake head-restrained mice, we show that ammonia rapidly compromises astrocyte potassium buffering, increasing extracellular potassium concentration and overactivating the Na(+)-K(+)-2Cl(-) cotransporter isoform 1 (NKCC1) in neurons. The consequent depolarization of the neuronal GABA reversal potential (EGABA) selectively impairs cortical inhibitory networks. Genetic deletion of NKCC1 or inhibition of it with the clinically used diuretic bumetanide potently suppresses ammonia-induced neurological dysfunction. We did not observe astrocyte swelling or brain edema in the acute phase, calling into question current concepts regarding the neurotoxic effects of ammonia. Instead, our findings identify failure of potassium buffering in astrocytes as a crucial mechanism in ammonia neurotoxicity and demonstrate the therapeutic potential of blocking this pathway by inhibiting NKCC1.
1] Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, University of Rochester, Rochester, New York, USA. [2] Letten Centre, Institute for Basic Medical Sciences, University of Oslo, Oslo, Norway. [3] Centre for Molecular Medicine Norway, University of Oslo, Oslo, Norway. [4] Department of Ophthalmology, Haukeland University Hospital, Bergen, Norway. [5].
Vinita
V
Rangroo Thrane
Alexander S
AS
Thrane
Fushun
F
Wang
Maria L
ML
Cotrina
Nathan A
NA
Smith
Michael
M
Chen
Qiwu
Q
Xu
Ning
N
Kang
Takumi
T
Fujita
Erlend A
EA
Nagelhus
Maiken
M
Nedergaard
D000641:Ammonia / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D011188:Potassium / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced* / Q000503:physiopathology
D000641:Ammonia; D011188:Potassium