Blocking early GABA depolarization with bumetanide results in permanent alterations in cortical circuits and sensorimotor gating deficits.
A high incidence of seizures occurs during the neonatal period when immature networks are hyperexcitable and susceptible to hypersyncrhonous activity. During development, γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in adults, typically excites neurons due to high expression of the Na(+)-K(+)-2Cl(-) cotransporter (NKCC1). NKCC1 facilitates seizures because it renders GABA activity excitatory through intracellular Cl(-) accumulation, while blocking NKCC1 with bumetanide suppresses seizures. Bumetanide is currently being tested in clinical trials for treatment of neonatal seizures. By blocking NKCC1 with bumetanide during cortical development, we found a critical period for the development of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate synapses. Disruption of GABA signaling during this window resulted in permanent decreases in excitatory synaptic transmission and sensorimotor gating deficits, a common feature in schizophrenia. Our study identifies an essential role for GABA-mediated depolarization in regulating the balance between cortical excitation and inhibition during a critical period and suggests a cautionary approach for using bumetanide in treating neonatal seizures.
Wang
Doris D
DD
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco CA 94143, USA. doris.wang@ucsf.edu
Kriegstein
Arnold R
AR
D000818:Animals; D002034:Bumetanide / Q000633:toxicity*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D051379:Mice; D055495:Neurogenesis / Q000187:drug effects*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D012640:Seizures / Q000503:physiopathology; D055139:Sensory Gating / Q000187:drug effects* / Q000502:physiology; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000633:toxicity*; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D064506:Solute Carrier Family 12, Member 2; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
C578878:Slc12a2 protein, mouse; D049994:Sodium Potassium Chloride Symporter Inhibitors; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D002034:Bumetanide; D005680:gamma-Aminobutyric Acid