Long-Term Potentiation in the Hippocampal CA1 Region Does Not Require Insertion and Activation of GluR2-Lacking AMPA Receptors

Gray, Erin E.; Fink, Ann E.; Sariñana, Joshua; Vissel, Bryce; O’Dell, Thomas J.

doi:10.1152/jn.00473.2007

Cited by 84 publications

(100 citation statements)

References 21 publications

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“…The reason TBP-LTP is so slow to develop remains obscure but does not depend on activity after the induction protocol (5). This makes it unlikely that it is due to NMDAR or AMPAR activity after LTP induction, consistent with prior reports (17,18).…”

Section: Resultssupporting

confidence: 79%

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.

133

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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Section: Resultssupporting

confidence: 79%

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.

133

126

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“…Thus, GluR2-lacking AMPARs might keep both LTP and spine expansion in a labile state whereas switching to GluR2-containing AMPARs stabilizes both forms of modifications. However, whether GluR2-lacking AMPARs underlie LTP expression remains highly controversial (20)(21)(22).In this study, we found that perisynaptic AMPARs are GluR2-lacking and switch to GluR2-containing after translocating to synapses. No reversal of LTP could be induced when GluR2-lacking AMPARs are present at synapses indicating that they are not sufficient to support reversal.…”

mentioning

confidence: 67%

“…4A). Chel or PKCI (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36) did not have any significant effects on basal synaptic transmission ( Fig. S4 A and C) or the size of naïve spines (Fig.…”

Section: Pkc Activity Is Required For the Full Expression Of Ltp But mentioning

confidence: 95%

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Perisynaptic GluR2-lacking AMPA receptors control the reversibility of synaptic and spines modifications

Yang

Wang

Zhou

2010

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

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How persistent synaptic and spine modification is achieved is essential to our understanding of developmental refinement of neural circuitry and formation of memory. Within a short period after their induction, both types of modifications can either be stabilized or reversed, but how this reversibility is controlled is largely unknown. We have shown previously that AMPA receptors (AMPARs) are delivered to perisynaptic regions after the induction of long-term potentiation (LTP) but are absent from perisynaptic regions after the full expression of LTP. Here, we report that perisynaptic AMPARs are GluR2-lacking and they translocate to synapses in a protein kinase C (PKC)-dependent manner. Once entering synapses, these AMPARs quickly switch to GluR2-containing in an activity-dependent manner. Absence of postinduction activity or blocking interactions between GluR2 and NSF, or GluR2 and GRIP/ PICK1 results in LTP mediated by GluR2-lacking AMPARs. However, these synaptic GluR2-lacking AMPARs are not sufficient to allow reversibility of LTP. On the other hand, postsynaptic inhibition of PKC activity holds AMPARs at perisynaptic regions. As long as perisynaptic AMPARs are present, both LTP and spine expansion remain labile: they can be reverted to the baseline state together with removal of perisynaptic AMPARs, or they can enter a stabilized state of persistent increase together with synaptic incorporation of perisynaptic AMPARs. Thus, perisynaptic GluR2-lacking AMPARs play a critical role in controlling the reversibility of both synaptic and spine modifications.dendritic spine | long-term potentiation | two-photon imaging P ersistent functional and structural changes in synaptic connections are generally believed to underlie long-lasting modifications in neuronal networks, such as developmental refinement of neural circuitry and memory formation in the adult (1-3). One widely studied form of such long-lasting changes is long-term potentiation (LTP), which is accompanied by long-lasting expansion of dendritic spines (2-4). Within a short time window after LTP induction, both types of modifications can be reversed (5, 6). What controls the labile period of these modifications is of great importance to our understanding of the consolidation of synaptic and spine modifications.Modification of existing synaptic AMPA receptors (AMPARs) and/or addition of new AMPARs to synapses appear to underlie the expression of LTP. Evidence supports a model that newly added AMPARs first appear at extrasynaptic/perisynaptic regions and are subsequently incorporated into synapses (7-11). These perisynaptic AMPARs can be removed by moderate synaptic activity (10) and this removal prevents the full expression of LTP and reverses spine expansion (6, 10). It has been suggested that perisynaptic AMPARs could play a critical role in regulating the persistence of LTP and spine expansion (10,12). This notion is consistent with the observation that stabilization of spine expansion requires synaptic incorporation of new AMPARs (6, 13). A few studies ...

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“…Although these receptors are subsequently replaced by GluR2-containing AMPARs, their transient expression in the synapse increases Ca 2ϩ permeability, and may contribute to the stabilization of LTP (Plant et al, 2006;Lu et al, 2007b). At later developmental stages GluR2-lacking AMPARs are no longer required for the early phase of LTP (Lu et al, 2007b), which may explain the discrepancies found in the literature concerning this issue (Adesnik and Nicoll, 2007;Gray et al, 2007). Under resting conditions AMPARs are recycled in a constitutive manner between synapses and intracellular membrane compartments, where they are sorted for degradation or for reinsertion at synapses (Ehlers, 2000;Passafaro et al, 2001) (see above).…”

Section: Role Of Ampars In Ltpmentioning

confidence: 99%

Regulation of AMPA receptors and synaptic plasticity

et al. 2009

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Long-Term Potentiation in the Hippocampal CA1 Region Does Not Require Insertion and Activation of GluR2-Lacking AMPA Receptors

Cited by 84 publications

References 21 publications

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

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

Perisynaptic GluR2-lacking AMPA receptors control the reversibility of synaptic and spines modifications

Regulation of AMPA receptors and synaptic plasticity

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