Long-term potentiation and contextual fear conditioning increase neuronal glutamate uptake

Levenson, Jonathan M.; Weeber, Edwin J.; Selcher, Joel C.; Kategaya, Lorna; Sweatt, J. David; Eskin, Arnold

doi:10.1038/nn791

Cited by 134 publications

(147 citation statements)

References 48 publications

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“…5A), consistent with the fact that high-affinity glutamate transporters on both neurons and glia are inhibited by TBOA and require extracellular Na for activity (4). Dihydrokainate (DHK), a selective GLT-1 inhibitor (4), decreased glutamate uptake by 35% in wild-type slices (mean Ϯ SEM: basal, 1275 Ϯ 75 fmol/ g/min; DHK, 830 Ϯ 93 fmol/ g/min), in agreement with previous studies (14), and by 42% in ephrin-A3-null slices (mean Ϯ SEM: basal, 1909 Ϯ 35 fmol/ g/min; DHK, 1104 Ϯ 121 fmol/ g/min) (Fig. 5A).…”

Section: Epha4 Activation Is Reduced In the Ephrin-a3-null Hippocampussupporting

confidence: 90%

“…To measure glutamate uptake, transverse acute hippocampal slices (300-m thickness) were equilibrated for 1 h at room temperature in oxygenated artificial cerebrospinal fluid (ACSF, 126 mM NaCl, 2.5 mM KCl, 1.2 mM NaH 2PO4, 1.3 mM MgCl2, 2.4 mM CaCl2, 26 mM NaHCO3, and 10 mM glucose), incubated for 7 min in ACSF containing 9.5 nM L-[ 3 H]-glutamate (0.5 Ci) and 100 M unlabeled glutamate, and then rapidly chilled on ice (14). Slices were then rinsed with cold ACSF and solubilized in 1% Triton X-100.…”

Section: Methodsmentioning

confidence: 99%

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Glial ephrin-A3 regulates hippocampal dendritic spine morphology and glutamate transport

Carmona

Murai

Wang

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

182

171

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Increasing evidence indicates the importance of neuron-glia communication for synaptic function, but the mechanisms involved are not fully understood. We reported that the EphA4 receptor tyrosine kinase is in dendritic spines of pyramidal neurons of the adult hippocampus and regulates spine morphology. We now show that the ephrin-A3 ligand, which is located in the perisynaptic processes of astrocytes, is essential for maintaining EphA4 activation and normal spine morphology in vivo. Ephrin-A3-knockout mice have spine irregularities similar to those observed in EphA4-knockout mice. Remarkably, loss of ephrin-A3 or EphA4 increases the expression of glial glutamate transporters. Consistent with this, glutamate transport is elevated in ephrin-A3-null hippocampal slices whereas Eph-dependent stimulation of ephrin-A3 signaling inhibits glutamate transport. Furthermore, some forms of hippocampus-dependent learning are impaired in the ephrin-A3-knockout mice. Our results suggest that the interaction between neuronal EphA4 and glial ephrin-A3 bidirectionally controls synapse morphology and glial glutamate transport, ultimately regulating hippocampal function.glial glutamate transporters ͉ hippocampus-dependent learning ͉ neuron-glia communication ͉ perisynaptic glial processes C ommunication between neurons and astrocytes plays an important role in synapse development and physiology. During development, astrocytes promote synapse formation and maturation (1, 2). Later on, astrocytes are actively involved in synaptic transmission by responding to synaptic activation and releasing gliotransmitters, which in turn modulate neuronal excitability and neurotransmission (1, 3). At excitatory synapses, astrocytes clear the majority of glutamate released into the synaptic cleft through their high-affinity transporters, GLAST and GLT-1 (4). This function is crucial for fine-tuning glutamatergic transmission and prevents accumulation of toxic levels of extracellular glutamate (5-7). Despite their importance in glutamate homeostasis, very little is known about the molecular mechanisms that regulate the expression and cell surface localization of glial glutamate transporters.Several members of the Eph family of receptor tyrosine kinases (comprising EphA and EphB receptors) and their cell surface-associated ephrin ligands are expressed in neurons of the hippocampus and cerebral cortex, where they have been implicated in synapse formation and the regulation of synaptic function and plasticity (8, 9). Signaling by Eph receptors is also involved in the development of dendritic spines, the specialized protrusions on dendrites that receive excitatory innervation. Typical spines have an enlarged head connected to the dendritic shaft by a constricted neck. Activation of dendritic EphB receptors by ephrin-B ligands has been shown to induce spine morphogenesis and maturation (8, 9). EphA receptors are important regulators of spine morphology in the adult. We have reported that EphA4 is localized on dendritic spines of pyramidal neurons in the m...

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Section: Epha4 Activation Is Reduced In the Ephrin-a3-null Hippocampussupporting

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Glial ephrin-A3 regulates hippocampal dendritic spine morphology and glutamate transport

Carmona

Murai

Wang

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

182

171

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“…These data obtained in C57BL/6 mice are in agreement with our previous work performed on Swiss mice (Benchenane et al, 2007), showing then the phenotypic consistency of the mechanism across these mouse strains. In addition, our present data reveal that, although NMDARs are involved in emotional memory (Levenson et al, 2002;Bardgett et al, 2003;Gao et al, 2010), the influence of tPA on this process cannot be explained by its ability to promote NMDAR-dependent signaling. It is well admitted that the establishment of emotional memory also involves BDNF (Liu et al, 2004b).…”

Section: Discussioncontrasting

confidence: 56%

GluN2D Subunit-Containing NMDA Receptors Control Tissue Plasminogen Activator-Mediated Spatial Memory

et al. 2012

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Tissue plasminogen activator (tPA) is a serine protease with pleiotropic actions in the CNS, such as synaptic plasticity and neuronal death. Some effects of tPA require its interaction with the GluN1 subunit of the NMDA receptor (NMDAR), leading to a potentiation of NMDAR signaling. We have reported previously that the pro-neurotoxic effect of tPA is mediated through GluN2D subunit-containing NMDARs. Thus, the aim of the present study was to determine whether GluN2D subunit-containing NMDARs drive tPA-mediated cognitive functions. To address this issue, a strategy of immunization designed to prevent the in vivo interaction of tPA with NMDARs and GluN2D-deficient mice were used in a set of behavioral tasks. Altogether, our data provide the first evidence that tPA influences spatial memory through its preferential interaction with GluN2D subunit-containing NMDARs.

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“…Synaptic uptake currents on astrocytes are not altered with LTP (22,23), but it has been proposed that LTP can induce increased uptake of bulk glutamate via EAAT2 and EAAT3 (24,25). The effect of TBOA that we have observed does not require either of these transporters, ruling out the findings of refs.…”

Section: Discussionsupporting

confidence: 56%

“…LTP induction is not thought to alter glutamate uptake near the synaptic cleft, because synaptic transporter currents in astrocytes are unchanged after LTP (22,23). However, it has been reported that bulk uptake of radiolabeled glutamate in CA1 is enhanced after LTP induction because of the increased function of EAAT3 shortly after induction and increased expression of EAAT2 at later periods (24,25). Thus, if TBOA facilitates the EPSP via blockade of EAAT2 or EAAT3, this might be explained by increased function of EAATs rather than newly inserted AMPARs.…”

Section: Resultsmentioning

confidence: 99%

Delivery of AMPA receptors to perisynaptic sites precedes the full expression of long-term potentiation

Yang

Wang

Frerking

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

131

126

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Trafficking of AMPA subtype glutamate receptors (AMPARs) from intracellular compartments to synapses is thought to be a major mechanism underlying the expression of long-term potentiation (LTP), a cellular substrate for learning and memory. However, it remains unclear whether the AMPAR trafficking that takes place during LTP is due to a targeted insertion of AMPARs directly into the synapse or delivery to extrasynaptic sites followed by translocation into the synapse. Here, we provide direct physiological evidence that LTP induced by a theta-burst pairing and tetanic stimulation protocols causes the rapid delivery of AMPARs to a perisynaptic site. Perisynaptic AMPARs do not normally detect synaptically released glutamate but can do so when the glial glutamate transporter EAAT1 is inhibited. AMPARs can be detected at this perisynaptic site before, but not after, the full expression of LTP. The appearance of perisynaptic AMPARs requires postsynaptic exocytosis, PKA signaling, and the C-terminal region of GluR1 subunit of AMPARs but not actin polymerization. Actin polymerization after LTP induction is required to retain AMPARs at the perisynaptic site after their appearance. Low-frequency stimulation given shortly after LTP induction leads to activity-dependent removal of perisynaptic AMPARs and suppresses the subsequent expression of LTP. These results demonstrate that AMPARs are rapidly trafficked to perisynaptic sites shortly after LTP induction and suggest that the delivery and maintenance of perisynaptic AMPARs may serve as a checkpoint in the expression of LTP.actin ͉ dendritic spine ͉ trafficking ͉ TBOA ͉ two-photon imaging A ctivity-induced modification of neuronal connections is essential for the development of the nervous system and may underlie some forms of learning and memory. One widely examined form of synaptic plasticity is long-term potentiation (LTP). LTP leads to the synaptic insertion of glutamate receptors of the AMPA subtype (AMPARs) (1-4). Recent studies also suggest that this synaptic incorporation of AMPARs may stabilize spine modifications associated with LTP (5, 6). Postsynaptic exocytosis (7,8), PKA activity (9), and AMPARs containing the GluR1 subunit (10) are implicated in the synaptic incorporation of AMPARs during LTP, but it remains unclear whether LTP leads to the direct insertion of AMPARs at the postsynaptic density (PSD) or to insertion at extrasynaptic regions followed by translocation into the PSD.Consistent with the latter idea, AMPAR targeting from intracellular compartments to the cell surface can occur via mechanisms that are distinct from AMPAR targeting from the cell surface to the synapse (11). By visualizing the movement of transfected AMPAR subunits or specific domains of AMPAR subunits in culture, trafficking of AMPARs can be observed in response to LTP induced by synaptic activity or chemical induction protocols. Using this approach, studies have found that AMPARs containing GluR1 can be inserted into the plasma membrane from intracellular stores (2). Lateral mobili...

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Long-term potentiation and contextual fear conditioning increase neuronal glutamate uptake

Cited by 134 publications

References 48 publications

Glial ephrin-A3 regulates hippocampal dendritic spine morphology and glutamate transport

Glial ephrin-A3 regulates hippocampal dendritic spine morphology and glutamate transport

GluN2D Subunit-Containing NMDA Receptors Control Tissue Plasminogen Activator-Mediated Spatial Memory

Delivery of AMPA receptors to perisynaptic sites precedes the full expression of long-term potentiation

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