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Glutamate synapse in developing brain: an integrative perspective beyond the silent state
Opinion
Glutamate synapse in developing brain: an integrative perspective beyond the silent state Eric Hanse1, Tomi Taira2, Sari Lauri2 and Laurent Groc3,4 1
Department of Physiology, Goteborg University, Goteborg 40530, Sweden Neuroscience Center and Department of Biosciences, P.O. Box 65, University of Helsinki, Helsinki FI-00014, Finland 3 Centre National de la Recherche Scientifique, Physiologie Cellulaire de la Synapse, UMR 5091, Bordeaux, France 4 Universite´ Bordeaux 2, 33077 Bordeaux, France 2
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 preand 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 Corresponding author: Groc, L. ([email protected]).
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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 preand postsynaptic plasticity of the glutamate synapse in the developing brain and to discuss how this plasticity can interact to promote synapse elimination/stabilization. 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 and NMDA receptors (NMDARs) [6–10]. Mean quantal properties of hippocampal synapses in the developing brain are surprisingly similar to those of synapses in the adult [11]. What is characteristic, however, for synapses in the developing brain is their functional lability, even to sparse activation [12–15] counteracted by Hebbian induction [12,13,16,17]. This lability, which can be expressed both pre- and postsynaptically, could then represent specific developmental plasticity of critical importance for the selection and elimination of developing synapses. Possible mechanisms explaining post- and the presynaptic involvement in this lability are the focus of this review. 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
0166-2236/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2009.07.003 Available online 4 September 2009
Opinion 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 [21–25] and that AMPARs are actually more abundant in the absence of functional NMDARs [20]. How can AMPARs be expressed at synapses in the developing brain whereas the majority of these synapses are AMPA silent? This apparent contradiction can be explained by the finding that glutamate synapses easily shift between an AMPA signaling and an AMPA silent state in an activity-dependent manner [12,13,26]. Although an inactive synapse retains its AMPA signaling capacity, synaptic activity, even at a low rate (a few releases/min), can render the synapse AMPA silent, whereas NMDA signaling is stable [13] (Figure 1a). Following AMPA silencing, the silent synapse can regain AMPA signaling either by prolonged (several minutes) stimulus interruption [12] (Figure 1a) or by NMDAR-dependent Hebbian induction [16,18,27,28] (Figure 1b). In contrast to Hebbian induction, prolonged stimulus interruption does not protect synapses from immediate renewed
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silencing. This on–off behavior of AMPA signaling decreases with development in the synaptic population to principal neurons [12,16,26] but is maintained at NMDAR-containing glutamate synapses to GABAergic interneurons [29]. What causes the AMPA lability of these hippocampal glutamate synapses? Although it remains to be investigated, AMPA silencing seems to be related to agonistinduced dispersal and possible subsequent internalization of synaptic AMPARs. Interestingly, it has been proposed that such a possibility would rely on glutamate bindinginduced changes in the interaction between AMPARs and TARPs [30,31]. Moreover, brief application of AMPA produces a large depression occluding stimulation-induced AMPA silencing in slices from neonatal rats (1–2 weeks) but little depression in slices from older (5–6 weeks) rats (Wasling et al. unpublished results; see also Ref. [32]). This finding is consistent with developmentally regulated susceptibility to agonist-induced dispersal of synaptic AMPARs. Several findings have also indicated that insertion or endocytosis and lateral trafficking of AMPARs are more active at developing neurons [8]. In addition, changes in filopodia or spine shape might cause changes in AMPAR retention [33]. However, the molecular mechanisms for
Figure 1. Instability of AMPA signaling and AMPA receptor surface mobility in immature neurons. (a) Lability of AMPA signaling of the CA3–CA1 connection of the developing hippocampus. The absence of evoked activity restores AMPAR-mediated transmission following test frequency-induced depression at 0.2 Hz at previously nonstimulated CA3–CA1 synapses. The top graph shows one experiment and the lower graph shows the average of six such experiments. Previously non-activated synapses were activated 120 times (at 0.2 Hz), stimulation was interrupted for 40 min and then test stimulation was resumed. Adapted with permission from Ref. [12]. (b) Hebbian induction restores AMPAR-mediated transmission following test frequency-induced depression at 0.2 Hz at previously non-stimulated CA3–CA1 synapses. Previously nonactivated synapses were activated 120 times (at 0.2 Hz), three high-frequency (50 Hz) stimulations (20 impulses) were applied and test stimulation was resumed. Adapted with permission from Ref. [16]. Note that although both the absence of evoked activity and Hebbian induction restores AMPAR-mediated transmission following test frequency-induced depression, Hebbian induction does this in a more stable manner. (c) Representative trajectories of diffusing AMPARs at the surface of immature (<8 days in vitro, left panel) and mature (>15 days in vitro, right panel) hippocampal cultured neurons. Postsynaptic densities were detected by expressing Homer-GFP (clusters). Note the labile behavior of surface AMPAR in a stubby synapse from immature neuron, whereas AMPARs are more stable in a spine synapse. The scale bar represent 5 mm on the left and 0.5 mm on the right.
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Opinion this greater susceptibility to agonist-induced synaptic removal of AMPARs early in development remain unclear. 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 glutamate synapse is born with or without AMPARs. If the glutamate synapse is born AMPA silent, with AMPARs acquired appreciably later by Hebbian induction, we could predict that this acquirement of AMPARs is explained by rapid and all-or-none insertion of an AMPAR packet or diffusion of a surface cluster, probably preceded by similar delivery of NMDARs. In immature neurons, NMDAR transport packets are mobile and recruited to axo-dendritic contacts within minutes [36], indicating that NMDARs can be inserted as packets to newly formed synapses. However, such packet membrane delivery is not specific for the synapse itself because a large proportion of these transport packets cycle through the dendritic plasma membrane at extrasynaptic locations [37], indicating that most surface NMDARs are inserted in the extrasynaptic membrane and diffuse on the surface to reach synaptic locations. AMPAR transport packets have also been described but were found to be less mobile than NMDAR packets [36]. Recruitment of AMPAR packets to nascent axo-dendritic contacts has not been reported, so it remains unclear whether AMPAR transport packets are inserted directly into nascent synapses or whether surface AMPAR clusters are laterally recruited. In contrast to NMDARs, AMPARs seem to be recruited to a nascent synapse in a gradual fashion, suggesting a discrete and non-(or small) packet delivery type [6], not fully consistent with the predicted rapid and all-or-none insertion of an AMPAR packet. For a glutamate synapse born with AMPA signaling, surface synaptic AMPARs would probably be unstable in the developing brain. When surface diffusion of GluR2AMPARs and NR1-NMDARs were compared during synaptogenesis, AMPAR surface diffusion was consistently higher than that of NMDARs and changes in neuronal activity affected only AMPAR surface diffusion [38]. These data suggest the presence of an unstable pool of surface AMPARs and a more stable pool of surface NMDARs. During in vitro development, surface diffusion of AMPARs located in the synaptic area decreased markedly (70%) with age, whereas NMDAR diffusion within the synaptic area was less affected (30%) (Figure 1c). These data are consistent with an increase in lateral recruitment and stabilization of AMPARs – and NMDAR to a lesser extent – with age both in vitro and in vivo [39,40]. Although the molecular mechanisms are still unclear, it has been reported that intracellular (e.g. TARP proteins [39]), extracellular (e.g. matrix [41]), and transynaptic (e.g. ephrins [42]) interactors are required for this 534
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developmental stabilization of glutamate receptors. Taken together, the results indicate that a characteristic feature of synapses early in development is lability of both surface and intracellular postsynaptic receptors that is compatible with the functional AMPA silencing–unsilencing scenario [8]. Trafficking of presynaptic glutamate receptors has been investigated to a lesser extent but it has recently been revealed that surface presynaptic neurotransmitter receptors are also quite mobile [43,44]. For instance, surface presynaptic NMDARs, detected early in development [45], seem to be more mobile than postsynaptic NMDARs [44,46], although a direct comparison is still lacking. The mechanisms regulating subcellular distribution of presynaptic kainate-type glutamate receptor (KAR) isoforms are still largely unclear, but probably depend on the cellular environment [47]. Identification of developmentally regulated proteins that interact with the cytoplasmic domains of KARs might reveal mechanisms for presynaptic KAR stabilization. Thus, although more studies are clearly needed, it seems that presynaptic glutamate receptors are quite dynamic and that their impact on synaptic activity in the developing brain, such as the effect of KAR activation on glutamate release [17] (see below), is most probably regulated in an age- and synapse-dependent manner. 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 scavenger leads to an increase in transmission, selective for low Pr synapses [17], resulting in a dramatic change in synaptic dynamics (Figure 2). Thus, analogously to the AMPA silencing in response to low levels of activity [13], low levels of ambient glutamate depress presynaptic efficacy at synapses in the developing brain, a mechanism that might contribute to the lability of transmission and to the presynaptic silence of synapses to low-frequency activation. The effect of a glutamate scavenger is mimicked and fully occluded by KAR antagonism [17,48], suggesting that the effect of ambient glutamate on release is mediated by presynaptic high-affinity KARs. Intriguingly, the tonic endogenous KAR activity is specifically expressed in area CA1 of the developing hippocampus and, in analogy with postsynaptic silence, is rapidly switched off by Hebbian induction [17] and by application of the brain-derived neurotrophic factor, BDNF [49]. In the first postnatal week, long-term potentiation (LTP) in area CA1 includes a presynaptic component according to changes observed in short-term plasticity [17,50,51]. Similar results have been obtained in neuronal cultures, where Hebbian type plasticity at low Pr synapses is associated with rapid changes in presynaptic structure and function [52]. The presynaptic LTP in response to Hebbian stimulation is
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Figure 2. Schematic representation of the multi-states of a glutamate synapse early in development. At immature hippocampal synapses, a high-affinity presynaptic KAR is tonically activated by ambient glutamate. Its inhibitory action on glutamate release leads to facilitatory transmission at these synapses in response to high-frequency stimulation. During development and/or in response to Hebbian induction, the high-affinity receptor is inactivated via a currently unknown mechanism. This leads to a switch from immature to adult-type transmission, characterized by more reliable information transfer and a non-facilitatory response to high-frequency stimulation (adapted with permission from Ref. [26]). In addition, postsynaptic signaling of glutamate synapse in immature neuronal network exhibits high lability that is counteracted by Hebbian activity. The postsynaptic signaling can alternate between different states, i.e. AMPA stable, AMPA labile and AMPA silent (no AMPAR), depending on the overall synaptic activity. Synaptic maturation should then be considered as a highly unstable and dynamic process that adapts to the environment (e.g. network activity) through changes in pre- and postsynaptic signaling. Consistent and repeated silencing of the transmission could ultimately lead to synapse elimination.
thus developmentally restricted and is associated with a loss of tonic presynaptic inhibition by ambient glutamate [17]. Thus, neonatal LTP seems to represent an activitydependent mechanism leading to more reliable transmission both pre- and postsynaptically. 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 presynaptically silent or participate in Hebbian activity leading to stabilization. What drives Hebbian activity in the developing synapses? During the neonatal period there is robust endogenous neural network activity in the hippocampus that involves glutamatergic activity and depolarizing GABAergic signaling [56]. This particular activity consists of short bursts of high-frequency firing that mainly occurs
synchronously in the CA3 and CA1 populations of neurons [57] and is restricted to the first ten postnatal days in rodents [56,58]. During this developmental period much of the endogenous glutamatergic activity at CA1 neurons occurs as high-frequency bursts during the synchronous activity of the network [59]. We propose that active synapses in phase with such burst activation experience Hebbian induction [17,50,60] and maintain their AMPA signaling. By contrast, synapses that are sporadically active out-of-phase with this endogenous activity might become AMPA silent. Tonic activation of presynaptic KARs, by primarily reducing release to random CA3 activity, would then prevent AMPA silencing while still allowing release when the synapse is active in phase with CA3–CA1 burst activity. Having participated in such Hebbian induction events, a synapse would then not only maintain its postsynaptic AMPA signaling, but would also, through the off-switch of the tonic presynaptic inhibition, increase its release and thus its subsequent impact on postsynaptic CA1 activation. In this manner, pre- and postsynaptic plasticity might co-operate to maintain the synapse. The propensity of the glutamate synapse to become AMPA silent by exposure to sporadic and out-of-phase activity disappears with age [12,13,16]. Such 535
Opinion age-dependent changes might depend on various growth factors and include changes in the scaffold proteins, extracellular matrix and adhesion molecules surrounding the synaptic cleft and/or spine shape. All these elements have been found to regulate glutamate receptor surface diffusion [33,39,46,61] and might thus play a key role in the increased retention of surface glutamate receptors with age. Thus, their unique plastic properties enable synapses in the developing brain to maintain their AMPA signaling only by having participated in cooperative neuronal activity, with synaptic activity outside this context leading to AMPA silencing and possible elimination. By operating on these plastic properties, the rhythmic network activity in the immature brain can then help to construct neuronal networks functional for processing sensory experience. Acknowledgements The authors are supported by the Centre National de la Recherche Scientifique (L.G.), the Fondation Recherche Me´dicale (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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Glutamate synapse in developing brain: an integrative perspective beyond the silent state Eric Hanse1, Tomi Taira2, Sari Lauri2 and Laurent Groc3,4 1
Department of Physiology, Goteborg University, Goteborg 40530, Sweden Neuroscience Center and Department of Biosciences, P.O. Box 65, University of Helsinki, Helsinki FI-00014, Finland 3 Centre National de la Recherche Scientifique, Physiologie Cellulaire de la Synapse, UMR 5091, Bordeaux, France 4 Universite´ Bordeaux 2, 33077 Bordeaux, France 2
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 preand 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 Corresponding author: Groc, L. ([email protected]).
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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 preand postsynaptic plasticity of the glutamate synapse in the developing brain and to discuss how this plasticity can interact to promote synapse elimination/stabilization. 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 and NMDA receptors (NMDARs) [6–10]. Mean quantal properties of hippocampal synapses in the developing brain are surprisingly similar to those of synapses in the adult [11]. What is characteristic, however, for synapses in the developing brain is their functional lability, even to sparse activation [12–15] counteracted by Hebbian induction [12,13,16,17]. This lability, which can be expressed both pre- and postsynaptically, could then represent specific developmental plasticity of critical importance for the selection and elimination of developing synapses. Possible mechanisms explaining post- and the presynaptic involvement in this lability are the focus of this review. 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
0166-2236/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2009.07.003 Available online 4 September 2009
Opinion 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 [21–25] and that AMPARs are actually more abundant in the absence of functional NMDARs [20]. How can AMPARs be expressed at synapses in the developing brain whereas the majority of these synapses are AMPA silent? This apparent contradiction can be explained by the finding that glutamate synapses easily shift between an AMPA signaling and an AMPA silent state in an activity-dependent manner [12,13,26]. Although an inactive synapse retains its AMPA signaling capacity, synaptic activity, even at a low rate (a few releases/min), can render the synapse AMPA silent, whereas NMDA signaling is stable [13] (Figure 1a). Following AMPA silencing, the silent synapse can regain AMPA signaling either by prolonged (several minutes) stimulus interruption [12] (Figure 1a) or by NMDAR-dependent Hebbian induction [16,18,27,28] (Figure 1b). In contrast to Hebbian induction, prolonged stimulus interruption does not protect synapses from immediate renewed
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silencing. This on–off behavior of AMPA signaling decreases with development in the synaptic population to principal neurons [12,16,26] but is maintained at NMDAR-containing glutamate synapses to GABAergic interneurons [29]. What causes the AMPA lability of these hippocampal glutamate synapses? Although it remains to be investigated, AMPA silencing seems to be related to agonistinduced dispersal and possible subsequent internalization of synaptic AMPARs. Interestingly, it has been proposed that such a possibility would rely on glutamate bindinginduced changes in the interaction between AMPARs and TARPs [30,31]. Moreover, brief application of AMPA produces a large depression occluding stimulation-induced AMPA silencing in slices from neonatal rats (1–2 weeks) but little depression in slices from older (5–6 weeks) rats (Wasling et al. unpublished results; see also Ref. [32]). This finding is consistent with developmentally regulated susceptibility to agonist-induced dispersal of synaptic AMPARs. Several findings have also indicated that insertion or endocytosis and lateral trafficking of AMPARs are more active at developing neurons [8]. In addition, changes in filopodia or spine shape might cause changes in AMPAR retention [33]. However, the molecular mechanisms for
Figure 1. Instability of AMPA signaling and AMPA receptor surface mobility in immature neurons. (a) Lability of AMPA signaling of the CA3–CA1 connection of the developing hippocampus. The absence of evoked activity restores AMPAR-mediated transmission following test frequency-induced depression at 0.2 Hz at previously nonstimulated CA3–CA1 synapses. The top graph shows one experiment and the lower graph shows the average of six such experiments. Previously non-activated synapses were activated 120 times (at 0.2 Hz), stimulation was interrupted for 40 min and then test stimulation was resumed. Adapted with permission from Ref. [12]. (b) Hebbian induction restores AMPAR-mediated transmission following test frequency-induced depression at 0.2 Hz at previously non-stimulated CA3–CA1 synapses. Previously nonactivated synapses were activated 120 times (at 0.2 Hz), three high-frequency (50 Hz) stimulations (20 impulses) were applied and test stimulation was resumed. Adapted with permission from Ref. [16]. Note that although both the absence of evoked activity and Hebbian induction restores AMPAR-mediated transmission following test frequency-induced depression, Hebbian induction does this in a more stable manner. (c) Representative trajectories of diffusing AMPARs at the surface of immature (<8 days in vitro, left panel) and mature (>15 days in vitro, right panel) hippocampal cultured neurons. Postsynaptic densities were detected by expressing Homer-GFP (clusters). Note the labile behavior of surface AMPAR in a stubby synapse from immature neuron, whereas AMPARs are more stable in a spine synapse. The scale bar represent 5 mm on the left and 0.5 mm on the right.
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Opinion this greater susceptibility to agonist-induced synaptic removal of AMPARs early in development remain unclear. 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 glutamate synapse is born with or without AMPARs. If the glutamate synapse is born AMPA silent, with AMPARs acquired appreciably later by Hebbian induction, we could predict that this acquirement of AMPARs is explained by rapid and all-or-none insertion of an AMPAR packet or diffusion of a surface cluster, probably preceded by similar delivery of NMDARs. In immature neurons, NMDAR transport packets are mobile and recruited to axo-dendritic contacts within minutes [36], indicating that NMDARs can be inserted as packets to newly formed synapses. However, such packet membrane delivery is not specific for the synapse itself because a large proportion of these transport packets cycle through the dendritic plasma membrane at extrasynaptic locations [37], indicating that most surface NMDARs are inserted in the extrasynaptic membrane and diffuse on the surface to reach synaptic locations. AMPAR transport packets have also been described but were found to be less mobile than NMDAR packets [36]. Recruitment of AMPAR packets to nascent axo-dendritic contacts has not been reported, so it remains unclear whether AMPAR transport packets are inserted directly into nascent synapses or whether surface AMPAR clusters are laterally recruited. In contrast to NMDARs, AMPARs seem to be recruited to a nascent synapse in a gradual fashion, suggesting a discrete and non-(or small) packet delivery type [6], not fully consistent with the predicted rapid and all-or-none insertion of an AMPAR packet. For a glutamate synapse born with AMPA signaling, surface synaptic AMPARs would probably be unstable in the developing brain. When surface diffusion of GluR2AMPARs and NR1-NMDARs were compared during synaptogenesis, AMPAR surface diffusion was consistently higher than that of NMDARs and changes in neuronal activity affected only AMPAR surface diffusion [38]. These data suggest the presence of an unstable pool of surface AMPARs and a more stable pool of surface NMDARs. During in vitro development, surface diffusion of AMPARs located in the synaptic area decreased markedly (70%) with age, whereas NMDAR diffusion within the synaptic area was less affected (30%) (Figure 1c). These data are consistent with an increase in lateral recruitment and stabilization of AMPARs – and NMDAR to a lesser extent – with age both in vitro and in vivo [39,40]. Although the molecular mechanisms are still unclear, it has been reported that intracellular (e.g. TARP proteins [39]), extracellular (e.g. matrix [41]), and transynaptic (e.g. ephrins [42]) interactors are required for this 534
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developmental stabilization of glutamate receptors. Taken together, the results indicate that a characteristic feature of synapses early in development is lability of both surface and intracellular postsynaptic receptors that is compatible with the functional AMPA silencing–unsilencing scenario [8]. Trafficking of presynaptic glutamate receptors has been investigated to a lesser extent but it has recently been revealed that surface presynaptic neurotransmitter receptors are also quite mobile [43,44]. For instance, surface presynaptic NMDARs, detected early in development [45], seem to be more mobile than postsynaptic NMDARs [44,46], although a direct comparison is still lacking. The mechanisms regulating subcellular distribution of presynaptic kainate-type glutamate receptor (KAR) isoforms are still largely unclear, but probably depend on the cellular environment [47]. Identification of developmentally regulated proteins that interact with the cytoplasmic domains of KARs might reveal mechanisms for presynaptic KAR stabilization. Thus, although more studies are clearly needed, it seems that presynaptic glutamate receptors are quite dynamic and that their impact on synaptic activity in the developing brain, such as the effect of KAR activation on glutamate release [17] (see below), is most probably regulated in an age- and synapse-dependent manner. 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 scavenger leads to an increase in transmission, selective for low Pr synapses [17], resulting in a dramatic change in synaptic dynamics (Figure 2). Thus, analogously to the AMPA silencing in response to low levels of activity [13], low levels of ambient glutamate depress presynaptic efficacy at synapses in the developing brain, a mechanism that might contribute to the lability of transmission and to the presynaptic silence of synapses to low-frequency activation. The effect of a glutamate scavenger is mimicked and fully occluded by KAR antagonism [17,48], suggesting that the effect of ambient glutamate on release is mediated by presynaptic high-affinity KARs. Intriguingly, the tonic endogenous KAR activity is specifically expressed in area CA1 of the developing hippocampus and, in analogy with postsynaptic silence, is rapidly switched off by Hebbian induction [17] and by application of the brain-derived neurotrophic factor, BDNF [49]. In the first postnatal week, long-term potentiation (LTP) in area CA1 includes a presynaptic component according to changes observed in short-term plasticity [17,50,51]. Similar results have been obtained in neuronal cultures, where Hebbian type plasticity at low Pr synapses is associated with rapid changes in presynaptic structure and function [52]. The presynaptic LTP in response to Hebbian stimulation is
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Figure 2. Schematic representation of the multi-states of a glutamate synapse early in development. At immature hippocampal synapses, a high-affinity presynaptic KAR is tonically activated by ambient glutamate. Its inhibitory action on glutamate release leads to facilitatory transmission at these synapses in response to high-frequency stimulation. During development and/or in response to Hebbian induction, the high-affinity receptor is inactivated via a currently unknown mechanism. This leads to a switch from immature to adult-type transmission, characterized by more reliable information transfer and a non-facilitatory response to high-frequency stimulation (adapted with permission from Ref. [26]). In addition, postsynaptic signaling of glutamate synapse in immature neuronal network exhibits high lability that is counteracted by Hebbian activity. The postsynaptic signaling can alternate between different states, i.e. AMPA stable, AMPA labile and AMPA silent (no AMPAR), depending on the overall synaptic activity. Synaptic maturation should then be considered as a highly unstable and dynamic process that adapts to the environment (e.g. network activity) through changes in pre- and postsynaptic signaling. Consistent and repeated silencing of the transmission could ultimately lead to synapse elimination.
thus developmentally restricted and is associated with a loss of tonic presynaptic inhibition by ambient glutamate [17]. Thus, neonatal LTP seems to represent an activitydependent mechanism leading to more reliable transmission both pre- and postsynaptically. 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 presynaptically silent or participate in Hebbian activity leading to stabilization. What drives Hebbian activity in the developing synapses? During the neonatal period there is robust endogenous neural network activity in the hippocampus that involves glutamatergic activity and depolarizing GABAergic signaling [56]. This particular activity consists of short bursts of high-frequency firing that mainly occurs
synchronously in the CA3 and CA1 populations of neurons [57] and is restricted to the first ten postnatal days in rodents [56,58]. During this developmental period much of the endogenous glutamatergic activity at CA1 neurons occurs as high-frequency bursts during the synchronous activity of the network [59]. We propose that active synapses in phase with such burst activation experience Hebbian induction [17,50,60] and maintain their AMPA signaling. By contrast, synapses that are sporadically active out-of-phase with this endogenous activity might become AMPA silent. Tonic activation of presynaptic KARs, by primarily reducing release to random CA3 activity, would then prevent AMPA silencing while still allowing release when the synapse is active in phase with CA3–CA1 burst activity. Having participated in such Hebbian induction events, a synapse would then not only maintain its postsynaptic AMPA signaling, but would also, through the off-switch of the tonic presynaptic inhibition, increase its release and thus its subsequent impact on postsynaptic CA1 activation. In this manner, pre- and postsynaptic plasticity might co-operate to maintain the synapse. The propensity of the glutamate synapse to become AMPA silent by exposure to sporadic and out-of-phase activity disappears with age [12,13,16]. Such 535
Opinion age-dependent changes might depend on various growth factors and include changes in the scaffold proteins, extracellular matrix and adhesion molecules surrounding the synaptic cleft and/or spine shape. All these elements have been found to regulate glutamate receptor surface diffusion [33,39,46,61] and might thus play a key role in the increased retention of surface glutamate receptors with age. Thus, their unique plastic properties enable synapses in the developing brain to maintain their AMPA signaling only by having participated in cooperative neuronal activity, with synaptic activity outside this context leading to AMPA silencing and possible elimination. By operating on these plastic properties, the rhythmic network activity in the immature brain can then help to construct neuronal networks functional for processing sensory experience. Acknowledgements The authors are supported by the Centre National de la Recherche Scientifique (L.G.), the Fondation Recherche Me´dicale (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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