GABA(A) receptor-mediated signaling alters the structure of spontaneous activity in the developing retina.
Ambient GABA modulates firing patterns in adult neural circuits by tonically activating extrasynaptic GABA(A) receptors. Here, we demonstrate that during a developmental period when activation of GABA(A) receptors causes membrane depolarization, tonic activation of GABA(A) receptors blocks all spontaneous activity recorded in retinal ganglion cells (RGCs) and starburst amacrine cells (SACs). Bath application of the GABA(A) receptor agonist muscimol blocked spontaneous correlated increases in intracellular calcium concentration and compound postsynaptic currents in RGCs associated with retinal waves. In addition, GABA(A) receptor agonists activated a tonic current in RGCs that significantly reduced their excitability. Using a transgenic mouse in which green fluorescent protein is expressed under the metabotropic glutamate receptor subtype 2 promoter to target recordings from SACs, we found that GABA(A) receptor agonists blocked compound postsynaptic currents and also activated a tonic current. GABA(A) receptor antagonists reduced the holding current in SACs but not RGCs, indicating that ambient levels of GABA tonically activate GABA(A) receptors in SACs. GABA(A) receptor antagonists did not block retinal waves but did alter the frequency and correlation structure of spontaneous RGC firing. Interestingly, the drug aminophylline, a general adenosine receptor antagonist used to block retinal waves, induced a tonic GABA(A) receptor antagonist-sensitive current in outside-out patches excised from RGCs, indicating that aminophylline exerts its action on retinal waves by direct activation of GABA(A) receptors. These findings have implications for how various neuroactive drugs and neurohormones known to modulate extrasynaptic GABA(A) receptors may influence spontaneous firing patterns that are critical for the establishment of adult neural circuits.
Wang
Chih-Tien
CT
Neurobiology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093, USA.
Blankenship
Aaron G
AG
Anishchenko
Anastasia
A
Elstrott
Justin
J
Fikhman
Michael
M
Nakanishi
Shigetada
S
Feller
Marla B
MB
D025042:Amacrine Cells / Q000187:drug effects / Q000502:physiology; D000628:Aminophylline / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D004347:Drug Interactions; D018682:GABA Agents / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018408:Patch-Clamp Techniques / Q000379:methods; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology*; D012160:Retina / Q000166:cytology* / Q000254:growth & development*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000502:physiology; D014795:Visual Pathways / Q000187:drug effects / Q000502:physiology*
D018682:GABA Agents; D010726:Phosphodiesterase Inhibitors; D011963:Receptors, GABA-A; D049452:Green Fluorescent Proteins; D000628:Aminophylline
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