Trends in Neurosciences
OpinionGlutamate synapse in developing brain: an integrative perspective beyond the silent state
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.
References (61)
How to build a central synapse: clues from cell culture
Trends Neurosci.
(2006)- et al.
Mechanisms of synapse assembly and disassembly
Neuron
(2003) Assembly of new individual excitatory synapses: time course and temporal order of synaptic molecule recruitment
Neuron
(2000)AMPA signalling in nascent glutamatergic synapses: there and not there!
Trends Neurosci.
(2006)Rapid functional maturation of nascent dendritic spines
Neuron
(2009)Functional maturation of CA1 synapses involves activity-dependent loss of tonic kainate receptor-mediated inhibition of glutamate release
Neuron
(2006)- et al.
Regulation of AMPA receptor recruitment at developing synapses
Trends Neurosci.
(2008) The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory
Cell
(1996)Evidence for silent synapses: implications for the expression of LTP
Neuron
(1995)Autoinactivation of neuronal AMPA receptors via glutamate-regulated TARP interaction
Neuron
(2009)
Glutamate receptor dynamics in dendritic microdomains
Neuron
The interaction between Stargazin and PSD-95 regulates AMPA receptor surface trafficking
Neuron
EphB receptors interact with NMDA receptors and regulate excitatory synapse formation
Cell
Tonic facilitation of glutamate release by presynaptic N-methyl-D-aspartate autoreceptors in the entorhinal cortex
Neuroscience
Subcellular localization and trafficking of kainate receptors
Trends Pharmacol. Sci.
Activity-induced rapid synaptic maturation mediated by presynaptic cdc42 signaling
Neuron
LTD induction causes morphological changes of presynaptic boutons and reduces their contacts with spines
Neuron
The classical complement cascade mediates CNS synapse elimination
Cell
AMPA receptor trafficking and synaptic plasticity
Annu. Rev. Neurosci.
Molecular mechanisms of presynaptic differentiation
Annu. Rev. Cell. Dev. Biol.
Dynamic aspects of CNS synapse formation
Annu. Rev. Neurosci.
Postsynaptic density assembly is fundamentally different from presynaptic active zone assembly
J. Neurosci.
Spine formation and correlated assembly of presynaptic and postsynaptic molecules
J. Neurosci.
Development of excitatory circuitry in the hippocampus
J. Neurophysiol.
Reversible synaptic depression in developing rat CA3 CA1 synapses explained by a novel cycle of AMPA silencing–unsilencing
J. Neurophysiol.
Creation of AMPA-silent synapses in the neonatal hippocampus
Nat. Neurosci.
Silent synapses in the developing hippocampus: lack of functional AMPA receptors or low probability of glutamate release? Proc
Natl. Acad. Sci. U. S. A.
Modulation of low-frequency-induced synaptic depression in the developing CA3–CA1 hippocampal synapses by NMDA and metabotropic glutamate receptor activation
J. Neurophysiol.
AMPA silencing is a prerequisite for developmental long-term potentiation in the hippocampal CA1 region
J. Neurophysiol.
Long-term potentiation and functional synapse induction in developing hippocampus
Nature
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