Coordinated Transitions in Neurotransmitter Systems for the Initiation and Propagation of Spontaneous Retinal Waves

Abstract

Spontaneous waves of excitation in the developing mammalian retina are mediated, to a large extent, by neurotransmission. However, it is unclear how the underlying neurotransmitter systems interact with each other to play specific roles in the formation of retinal waves at various developmental stages. In particular, it is puzzling why the waves maintain a similar propagation pattern even after underlying neurotransmitter systems have undergone drastic developmental changes. Using Ca 2ϩ imaging and patch clamp in a whole-mount preparation of the developing rabbit retina, we discovered two dramatic and coordinated transitions in the excitatory drive for retinal waves: one from a nicotinic to a muscarinic system, and the other from a fast cholinergic to a fast glutamatergic input. Retinal waves before the age of postnatal day 1 (P1) were blocked by nicotinic antagonists, but not by muscarinic or glutamatergic antagonists. After P3, however, the spontaneous wave, whose basic spatiotemporal pattern remained similar, was completely inhibited by muscarinic or glutamate antagonists, but not by nicotinic antagonists. We also found that the muscarinic drive, mediated primarily by M1 and M3 receptors, was particularly important for wave propagation, whereas the glutamatergic drive seemed more important for local excitation. Our results suggest (1) a novel mechanism by which a neurotransmitter system changes its functional role via a switch between two completely different classes of receptors for the same transmitter, (2) the cholinergic system plays a critical role in not only early but also late spontaneous waves, and (3) the continued participation of the cholinergic system may provide a network basis for the consistency in the overall propagation pattern of spontaneous retinal waves. Key words: visual development; spontaneous retinal waves; cholinergic amacrine cells; nicotinic and muscarinic receptors; glutamate receptors; calcium imaging; patch-clamp; rabbit retinaIn the developing vertebrate retina, rhythmic excitation occurs spontaneously among ganglion and amacrine cells and propagates laterally in local domains in the form of waves (for review, see

Disruption and Recovery of Patterned Retinal Activity in the Absence of Acetylcholine

“…To explore how synaptic networks in wt retina adjust to acute nicotinic receptor blockade, we applied DH␤E to wt retinas in vitro (n ϭ 6 retinas) for several hours and recorded their spiking activity. As in previous studies (Feller et al, 1996;Wong et al, 1998Wong et al, , 2000Bansal et al, 2000;Sernagor et al, 2000;Zhou and Zhao, 2000), synchronous bursting activity was abolished and most recording sites were silent within minutes of DH␤E application (Fig. 6 A).…”

“…Retinal structure develops normally in the absence of local ACh release Functional cholinergic pathways are present in the developing retina even before synaptic circuits are established (Yamashita et al, 1994;Wong, 1995;Zhou and Zhao, 2000;Feller, 2002;Pearson et al, 2002). ACh has been implicated in regulating local and global changes in the structural maturation of the retina.…”

“…Pharmacological studies show that the circuitry underlying synchronized activity alters systematically with development. Before synaptogenesis, gap junctions are responsible (Peinado et al, 1993;Catsicas et al, 1998;Wong et al, 1998;Roerig and Feller, 2000;Syed et al, 2004b), but after synapse formation, chemical neurotransmission drives correlated activity (Leinekugel et al, 1997;O'Donovan et al, 1998;O'Donovan, 1999;Bansal et al, 2000;Wong et al, 2000;Zhou and Zhao, 2000;Syed et al, 2004b). In the spinal cord and retina, synchronized activity is first dependent on cholinergic transmission and thereafter on glutamatergic transmission.…”

The role of nAChR‐mediated spontaneous retinal activity in visual system development

“…This activity is initially mediated by cholinergic circuits and then by glutamatergic circuits (Wong, 1999;Zhou and Zhao, 1999;Bansal et al, 2000;Zhou and Zhao, 2000). Several experimental results indicate that waves mediated by cholinergic circuits require the activation of nAChRs.…”

“…Second, the periodic calcium increases, action potentials, and compound postsynaptic currents associated with waves can all be blocked by a variety of nAChRs antagonists [ Fig. 2(B)] (Feller et al, 1996;Penn et al, 1998;Sernagor and Grzywacz, 1999;Bansal et al, 2000;Zhou and Zhao, 2000). Third, simultaneous recordings from rabbit starburst amacrine cells and RGCs show that the cholinergic starburst cells that synapse onto RGCs undergo spontaneous depolarizations that are correlated with the depolarizations of neighboring RGCs (Zhou, 1998) These recordings also show that, like RGCs, starburst amacrine cells themselves are excited via synaptic input during waves.…”