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Journal of Physiology (2002), 542.3, p. 665
© Copyright 2002 The Physiological Society
DOI: 10.1113/jphysiol.2002.025544
As the central nervous system develops and matures, receptors at excitatory and inhibitory synapses change their functional properties. There is a general trend from slow synaptic currents in the immature CNS, to fast currents at mature synapses. Synaptic currents mediated by AMPA, NMDA, GABAA and glycine receptors all become faster during development. Many other changes in synaptic properties occur concurrently, including a decrease in the calcium permeability of AMPA receptors, and a negative shift in the chloride reversal potential, which converts GABAA and glycine receptors from excitatory to inhibitory (Ben-Ari et al. 1997; Betz et al. 1999). Presumably, these functional changes address the practical challenges faced by developing neurons. As maturation progresses, fast synaptic transients become increasingly important for efficient information processing, and for tasks that require precise timing (e.g. sound localisation and motor coordination). Calcium-permeable AMPA and NMDA receptors mediate postsynaptic calcium influx, which plays a crucial role in adjusting the strength of excitatory synapses. Synaptic plasticity (and calcium-permeable receptors) are more important early in development. Glycine and GABAA receptors at immature synapses are excitatory, and can produce calcium influx through voltage-gated channels, or simultaneously activated NMDA receptors (Ben-Ari et al. 1997). Although calcium influx is important for synaptic plasticity and assembly of the postsynaptic density (Betz et al. 1999), it remains unclear whether it triggers postsynaptic receptor maturation.
The maturation of postsynaptic receptors results primarily from changes in the subunits from which they are constructed. Receptor subunits which impart slow kinetics tend to be expressed early in development, but are then replaced by 'faster' subunits. An important question in developmental neurobiology is what triggers these changes in receptor subunit expression? One appealing hypothesis is that receptor maturation is triggered by the activity of the receptors themselves. In this view, maturation does not occur until appropriate synaptic connections have formed and become active. Supporting evidence has been reported in neurons of the brainstem cochlear nucleus, where excitatory synapse formation triggers a reduction in AMPA receptor subunit 2 (GluR2) expression. This reduction is prevented by isolating the neurons in cell culture (Lawrence & Trussell, 2000). Chronic NMDA treatment induces NMDA receptor maturation in cultured cerebellar granule neurons, whereas chronic treatment with an NMDA antagonist blocks the developmental up-regulation of NMDA receptor subunit 1 (NR1) in the superior colliculus of young rats (Aamodt & Constantine-Paton, 1999).
A paper in this issue of The Journal of Physiology by Mangin et al. (2002) challenges the common view that receptor activation regulates subunit expression. They show that receptor maturation can occur in the absence of any detectable activation. They studied glycine receptors (GlyRs) in dopaminergic neurons of the rat substantia nigra pars compacta (SNc). These neurons receive no glycinergic synaptic inputs. No strychnine-sensitive currents were detected following afferent stimulation, elevation of extracellular potassium, application of hyposmotic solution, or blockade of taurine transporters. None the less, application of glycine evoked large currents (up to 1 nA) in these neurons. The subunit makeup of the GlyRs was characterised using single channel recordings and pharmacological tests. In neonatal rats (postnatal days (P) 7-10), the GlyRs were predominantly 
2 homomers, but by P19 the SNc neurons were expressing 1/
heteromeric GlyRs. This is the standard developmental switch seen in GlyRs of the brainstem and spinal cord. In these regions, the increased expression of subunits helps to cluster the GlyRs at the maturing postsynaptic density, via an interaction with the intracellular protein gephyrin (Legendre, 2001). Clearly, GlyR maturation does not serve this purpose in SNc neurons, as they do not receive glycinergic inputs. Intriguingly, these neurons exhibited a transient decrease in glycine responsiveness around P17, presumably as a result of the switch in subunit expression (Fig. 1).
Although Mangin et al. (2002) convincingly show that synaptic activation of glycine receptors is not required for receptor maturation, they do not propose an alternative explanation. One possibility is that calcium influx mediated by activation of GABAA or NMDA receptors could trigger the change in GlyR subunit expression. For comparison, chronic NMDA application increases the expression of several GABAA receptor subunits in cerebellar granule neurons (Aamodt & Constantine-Paton, 1999). But it is also possible that GlyR maturation is independent of external signals, and is controlled by an internal developmental schedule. It has been argued that the expression of GABAA receptor subunits is governed by an intrinsic programme that produces a specific spatial distribution by embryonic day 20 (E20) in rat neocortex, before axonal projections from other regions have arrived (Paysan & Fritschy, 1998). However, local synaptic contacts that could regulate subunit expression may already have formed. Regardless of what actually drives maturation, the developmental expression pattern of the GABAA receptor subunits 1, 2 and 5, is similar in rodents and primates, indicating that the overall regulation of receptor subtypes is conserved across species (Paysan & Fritschy, 1998). In summary, the spatial and temporal pattern of receptor subunit expression is most likely determined by an intrinsic genetic programme that can be modulated by synaptic activity and other external factors.
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REFERENCES
AAMODT, S.M. & CONSTANTINE-PATON, M. (1999). Advances in Neurology 79, 133-144.
[Medline]
BEN-ARI, Y., KHAZIPOV, R., LEINEKUGEL, X., CAILLARD, O. & GAIARSA, J.L. (1997). Trends in Neurosciences 20, 523-529.
[Medline]
BETZ, H., KUHSE, J., SCHMIEDEN, V., LAUBE, B., KIRSCH, J. & HARVEY, R.J. (1999). Annals of the New York Academy of Sciences 868, 667-676.
[Medline]
LAWRENCE, J.J. & TRUSSELL, L.O. (2000). Journal of Neuroscience 20, 4864-4870.
[Abstract/Full Text]
LEGENDRE, P. (2001). Cellular and Molecular Life Sciences 58, 760-793.
[Medline]
MANGIN, J.M., GUYON, A., EUGENE, D., PAUPARDIN-TRITSCH, D. & LEGENDRE, P. (2002). Journal of Physiology 542, 685-697.
[Abstract/Full Text]
PAYSAN, J. & FRITSCHY, J.M. (1998). Perspectives in Developmental Neurobiology 5, 179-192.
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