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The Journal of Neuroscience, August 22, 2007, 27(34):9130-9140; doi:10.1523/JNEUROSCI.1293-07.2007

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Development/Plasticity/Repair
GABA_A Receptor-Mediated Signaling Alters the Structure of Spontaneous Activity in the Developing Retina

Chih-Tien Wang,¹ Aaron G. Blankenship,^1,2 * Anastasia Anishchenko,^1 * Justin Elstrott,¹ Michael Fikhman,¹ Shigetada Nakanishi,^3,4 and Marla B. Feller¹

¹Neurobiology Section, Division of Biological Sciences and ²Neurosciences Graduate Program, University of California, San Diego, La Jolla, California 92093, ³Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan, and ⁴Department of Molecular and System Biology, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan

Correspondence should be addressed to Marla B. Feller, Neurobiology Section 0357, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0357. Email: mfeller{at}ucsd.edu

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.

Key words: spontaneous activity; retinal waves; retinal ganglion cell; starburst amacrine cell; aminophylline; adenosine receptor

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Received March 22, 2007; revised June 28, 2007; accepted June 29, 2007.

Correspondence should be addressed to Marla B. Feller, Neurobiology Section 0357, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0357. Email: mfeller{at}ucsd.edu

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