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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.

Pubmed ID: 20624842

Authors

  • Wang DD
  • Kriegstein AR

Journal

Cerebral cortex (New York, N.Y. : 1991)

Publication Data

March 21, 2011

Associated Grants

  • Agency: NINDS NIH HHS, Id: R01 NS021223

Mesh Terms

  • Animals
  • Bumetanide
  • Cerebral Cortex
  • Excitatory Postsynaptic Potentials
  • Inhibitory Postsynaptic Potentials
  • Mice
  • Neurogenesis
  • Organ Culture Techniques
  • Patch-Clamp Techniques
  • Seizures
  • Sensory Gating
  • Sodium Potassium Chloride Symporter Inhibitors
  • Sodium-Potassium-Chloride Symporters
  • Solute Carrier Family 12, Member 2
  • Synaptic Transmission
  • gamma-Aminobutyric Acid