9 Lui, Neff, & Berg, Science, 2006

9 Lui Neff, - REPORTS Sequential Interplay of Nicotinic and GABAergic Signaling Guides Neuronal Development Zhaoping Liu Robert A Neff Darwin K

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Sequential Interplay of Nicotinic and GABAergic Signaling Guides Neuronal Development Zhaoping Liu, Robert A. Neff, Darwin K. Berg* GABA ( g -aminobutyric acid), the major inhibitory transmitter in the brain, goes through a transitory phase of excitation during development. The excitatory phase promotes neuronal growth and integration into circuits. We show here that spontaneous nicotinic cholinergic activity is responsible for terminating GABAergic excitation and initiating inhibition. It does so by changing chloride transporter levels, shifting the driving force on GABA-induced currents. The timing of the transition is critical, because the two phases of GABAergic signaling provide contrasting developmental instructions. Synergistic with nicotinic excitation, GABAergic inhibition constrains neuronal morphology and innervation. The results reveal a multitiered activity-dependent strategy controlling neuronal development. G ABA ( g -aminobutyric acid) is the main inhibitory neurotransmitter in the adult brain, but GABAergic transmission is excitatory during early stages of development because of a reversed chloride gradient ( 1 3 ). The GABAergic excitatory period is critical for neuronal maturation and integration into circuits during embryonic development and after adult neurogenesis ( 2 , 4 6 ). Despite the profound impact of the GABAergic excitation/inhibition transition on the nervous system, little is known about mechanisms that determine the timing of the transition or about possible develop- mental consequences of subsequent inhibitory GABAergic input. We show here that endoge- nous nicotinic cholinergic activity drives matu- ration of GABAergic signaling, determining when it becomes inhibitory. Further, early GABAergic inhibition interacts synergistically with nicotinic cholinergic signaling to guide subsequent development in new directions. These are unexpected consequences of sponta- neous nicotinic activity. Pharmacological blockade of nicotinic ace- tylcholine receptors (nAChRs) in vivo revealed the effects of spontaneous nicotinic cholinergic activity on GABAergic maturation. An inform- ative example is the chick ciliary ganglion (CG), which receives nicotinic synaptic input from the accessory oculomotor nucleus and innervates smooth and striated muscle in the eye ( 7 ). In ad- dition to nAChRs, CG neurons express GABA A receptors ( 8 ) and, we find, receive GABAergic input (fig. S1). GABAergic excitation in devel- oping neurons can be visualized by loading cells with the calcium fluor fluo-3AM and challeng- ing with GABA ( 9 ). The resulting depolarization triggers calcium influx through voltage-gated calcium channels (VGCCs), causing fluores- cence. GABA induced fluorescent responses in freshly dissociated embryonic day 9 (E9) CG neurons loaded with fluo-3AM (Fig. 1, A to C). Fewer neurons from older ganglia displayed
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This note was uploaded on 10/30/2010 for the course BIPN BIPN 140 taught by Professor Spitzer during the Fall '07 term at UCSD.

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9 Lui Neff, - REPORTS Sequential Interplay of Nicotinic and GABAergic Signaling Guides Neuronal Development Zhaoping Liu Robert A Neff Darwin K

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