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EDITORIAL FOCUS
). However, it remains unclear how many immature excitatory synapses (i.e., ones that utilize glutamate as a neurotransmitter) participate in the relay of activity. Contributing to this problem is the finding that immature glutamatergic synapses are comprised largely of N-methyl-D-aspartate (NMDA) receptors and lack AMPA receptors that mediate fast excitatory transmission. Such synapses are said to be "silent," incapable of causing postsynaptic action potentials from resting levels because in addition to glutamate, the NMDA receptor requires membrane depolarization to relieve a voltage-dependent Mg2+ block. How then do silent synapses "speak" loudly enough to cause postsynaptic firing and thereby successfully relay information? In a recent article, Liu and Chen (2008) provide some answers to this question. They examine the synaptic responses and intrinsic properties of developing neurons by making use of an in vitro thalamic slice preparation that maintains the excitatory synaptic connections between retinal ganglion cells and relay cells of the dorsal lateral geniculate nucleus (LGN). In an elegant series of whole cell recording experiments, they show how a constellation of properties, including ligand-gated channel kinetics, receptor subunit composition, extended presence of neurotransmitter at the synapse, and intrinsic membrane properties, work in concert to promote spike firing and the faithful relay of retinal activity to visual cortex.
At face value, immature retinogeniculate synapses should remain silent or barely converse above a whisper. They produce extremely weak synaptic currents that are mediated almost entirely by NMDA receptor activation (Chen and Regehr 2000; Hooks and Chen 2006). Why then are postsynaptic responses evoked by the electrical activation of their retinal afferents able to give rise to reliable and precise patterns of spiking? In part, the answer lies in the subunit composition of their NMDA receptors. NMDA responses at immature retinogeniculate synapses have much slower decay times and a highly relaxed voltage-dependent Mg2+ blockade. Such kinetics are due to a unique subunit composition of the NMDA receptor, one that contains a prevalence of NR2B as well as NR2C/D receptor subunits. Liu and Chen also show that some immature synapses possess a small AMPA current. These, too, have much longer decay times compared with their mature counterparts due to an extended time course of active glutamate at the synapse. Finally, immature relay cells are inherently more excitable than mature neurons (see also Macleod et al. 1997). They have higher input resistance, reside at more depolarized membrane levels, and possess weaker K+ currents. Taken together, these features promote sustained levels of membrane depolarization and increase the likelihood that synaptically evoked events will give rise to spike firing.
Despite this arrangement, the synaptic current associated with the activation of a single retinal input may still be too weak to drive an immature relay cell to fire (Hooks and Chen 2006; Liu and Chen 1997). Instead, they seem designed to respond best to trains of presynaptically generated action potentials arising from the repetitive activation of a single retinal fiber or the co-activation of convergent ones. Indeed, while mature relay cells receive just one or two retinal inputs, immature cells are known to receive as many as one to two dozen inputs (Chen and Regehr 2000; Jaubert-Miazza et al. 2005). Thus an added dimension to the functional state of immature relay neurons is the pattern of connectivity provided by developing retinal ganglion cells. What is the driving force behind such co-activation? The answer lies in the spatiotemporal patterning of spontaneous retinal ganglion cell activity. Early in development, prior to the maturation of connections between photoreceptors and bipolar cells, neighboring retinal ganglion cells fire synchronously in well-coordinated bursts that traverse across the retina in a wave-like fashion (Demas et al. 2003; Wong 1999). These retinal waves lead to robust postsynaptic activity among LGN cells (Mooney et al. 1996), and the ensuing spikes are transmitted to the developing visual cortex (Haganu et al. 2006). This faithful relay of signals plays a vital role in the developmental remodeling of thalamocortical circuits. Without retinal waves, topographic maps (Cang et al. 2005) and cortical cell receptive field structure fail to develop properly (Huberman et al. 2006).
Thus this work provides important insight into the biophysical mechanisms by which immature excitatory synapses can transmit signals critical for the activity dependent maturation of circuits.
Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, Richmond, Virginia
Address for reprint requests and other correspondence: Dept. of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, Richmond, VA 23298-0709 (E-mail: wguido{at}vcu.edu)
REFERENCES
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Jaubert-Miazza L, Green E, Lo FS, Bui K, Mills J, Guido W. Structural and functional composition of the developing retinogeniculate pathway in the mouse. Vis Neurosci 22: 661–676, 2005.[Web of Science][Medline]
Liu X, Chen C. Different roles for AMPA and NMDA receptors in transmission at the immature retinogeniculate synapse. J Neurophysiol.doi:10.1152/jn.01171.2007.
MacLeod N, Turner C, Edgar J. Properties of developing lateral geniculate neurones in the mouse. Int J Dev Neurosci 15: 205–224, 1997.[CrossRef][Web of Science][Medline]
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