Trends in Neurosciences
Volume 32, Issue 10, October 2009, Pages 532-537
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Glutamate synapse in developing brain: an integrative perspective beyond the silent state

https://doi.org/10.1016/j.tins.2009.07.003Get rights and content

Cellular events underlying the establishment of glutamate transmission have been the focus of attention because appropriate wiring of developing neuronal networks is essential for adult brain functions. Although establishment of a synapse is a dynamic process requiring axonal and dendritic refinements, the functional interplay between pre- and postsynaptic signaling is often ignored. Here, we discuss recent data on pre- and postsynaptic plasticity of the glutamate synapse in the developing brain. The key aspect of the proposed model is that developing synapses are functionally labile in response to activity and this lability is counteracted by Hebbian activity. Both presynaptic and postsynaptic (loss of AMPA receptor signaling) mechanisms contribute to lability. Therefore, synapses in the developing brain maintain their capacity for functional AMPA signaling either by being presynaptically silent or by having participated in Hebbian activity; any synaptic activity outside this context leads instead to AMPA silencing and possible synaptic elimination.

Introduction

During brain development up to puberty there is enormous generation of synaptic connections. Synaptogenesis per se proceeds in an activity-independent manner and guidance molecules ensure that pre- and postsynaptic partnerships are established in the appropriate brain region [1]. Activity-dependent mechanisms then help in formation of the more precise mature pattern of synaptic connectivity, consisting of synapses that avoid elimination by proper participation in neuronal network activity. This arrangement allows testing of a large number of pre- and postsynaptic partnerships to fine-tune networks. During this developmental period, synapses are particularly prone to elimination [2] and it is likely that Hebbian-type plasticity mechanisms, which differ from those in the mature nervous system in some important respects, are of critical importance in the ongoing balance between synapse elimination and stabilization. Synaptic plasticity in the mature nervous system involves changes in the number of functional AMPA receptors (AMPARs) in the postsynaptic membrane, resulting in variability in transmission efficacy within the synapse population [3]. In the developing brain, synapses also alternate between an AMPA signaling and an AMPA silent state (with no functional postsynaptic AMPARs) in an activity-dependent manner, providing additional plasticity for neuronal connection refinements. Although establishment of a synapse is a dynamic process requiring both axonal and dendritic refinements, the functional interplay between pre- and postsynaptic signaling is often ignored. Focusing on the CA3–CA1 synapse in the developing (first two postnatal weeks) rodent hippocampus, the purpose of the present article is to review current data on both pre- and postsynaptic plasticity of the glutamate synapse in the developing brain and to discuss how this plasticity can interact to promote synapse elimination/stabilization.

Section snippets

The glutamate synapse in the developing brain: a brief overview

During the first stages of synaptogenesis, assembly of presynaptic specializations is guided by cellular and molecular events that are independent of neuronal activity 4, 5. The initial recruitment of the molecular components occurs rapidly and leads to the formation of presynaptic specialization capable of neurotransmitter release. Postsynaptically, nascent synapses are equipped, with some delay (within minutes to hours after morphological establishment of synaptic contact) with both AMPARs

Postsynaptic silencing and unsilencing

One of the hallmarks of developing networks is the presence of postsynaptically AMPA silent synapses (NMDA only synapses), which can acquire AMPARs via NMDAR-dependent Hebbian induction 18, 19. It is a matter of debate whether the synapse is born without AMPARs and whether NMDAR-dependent Hebbian induction is necessary for AMPAR recruitment to the nascent synapse 8, 19, 20. However, later studies revealed that there is no need for functional NMDARs for synaptic accumulation of AMPARs 21, 22, 23

Trafficking of glutamate receptors in the developing brain: dynamic to what extent?

Trafficking of glutamate receptors has been identified as a fundamental property in the regulation of synaptic efficacy [3]. It is now well established that receptors undergo trafficking to and from the plasma membrane through exocytosis and endocytosis, respectively, and diffuse laterally when inserted into the plasma membrane 34, 35. There are then multiple paths to regulate the content of synaptic receptors and associated proteins. As indicated above, it is a matter of debate whether the

Presynaptic mechanisms

Compared to the wealth of data on postsynaptic mechanisms, relatively little is known about age-dependent differences in presynaptic function that might contribute to lability of transmission in the developing brain. However, recent studies have shown that in the first postnatal week, but not after the second week, endogenous glutamate can tonically restrain presynaptic function by maintaining a low release probability at CA3–CA1 synapses 17, 48. Removal of glutamate by an enzymatic glutamate

Integrative model of the glutamate synapse in the developing brain

We propose that the unique functional lability of developing synapses is a prerequisite for the activity-dependent tuning process determining whether a given synapse survives or not, that is whether it is stabilized or eliminated (Figure 2). The AMPA silent state might be the initial step necessary for elimination 53, 54 by leaving the synapse exposed to subsequent physical elimination [55]. To avoid AMPA silencing and consequent elimination, the newborn synapse should then either be

Acknowledgements

The authors are supported by the Centre National de la Recherche Scientifique (L.G.), the Fondation Recherche Médicale (L.G.), the Agence Nationale Recherche (L.G.), the Swedish Research Council (E.H.), The Academy of Finland (S.L., T.T), the University of Helsinki (S.L) and the Sigrid Juselius Foundation (S.L., T.T). We thank staff members from our laboratories for critical discussions and apologize to those whose work was not cited because of space limitations.

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