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Permeable AMPA Receptors at Perisynaptic Sites by Glur1-S845 Phosphorylation

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Permeable AMPA Receptors at Perisynaptic Sites by Glur1-S845 Phosphorylation Stabilization of Ca2؉-permeable AMPA receptors at perisynaptic sites by GluR1-S845 phosphorylation Kaiwen Hea,b, Lihua Songa, Laurel W. Cummingsa, Jonathan Goldmanb, Richard L. Huganirc,1, and Hey-Kyoung Leea,b,1 aDepartment of Biology, College of Chemical and Life Sciences and bNeuroscience and Cognitive Science (NACS) Program, University of Maryland, College Park, MD 20742; and cSolomon H. Snyder Department of Neuroscience, Howard Hughes Medical Institute, Johns Hopkins School of Medicine, Baltimore, MD 21210 Contributed by Richard L. Huganir, September 25, 2009 (sent for review July 23, 2009) AMPA receptor (AMPAR) channel properties and function are regulates perisynaptic AMPAR subunit composition by stabi- regulated by its subunit composition and phosphorylation. Cer- lizing GluR1 homomers, and that LTD is associated with the .tain types of neural activity can recruit Ca2؉-permeable (CP) removal of CP-AMPARs AMPARs, such as GluR1 homomers, to synapses likely via lateral diffusion from extrasynaptic sites. Here we show that GluR1- Results S845 phosphorylation can alter the subunit composition of CP-AMPARs at Perisynaptic Sites of Schaffer Collateral Inputs to CA1. perisynaptic AMPARs by providing stability to GluR1 homomers. Using the property that CP-AMPARs are sensitive to applica- Using mice specifically lacking phosphorylation of the GluR1- tion of an exogenous polyamine philanthotoxin-433 (PhTX), we S845 site (GluR1-S845A mutants), we demonstrate that this site tested the presence of these receptors at Schaffer collateral is necessary for maintaining CP-AMPARs. Specifically, in the synapses on CA1 neurons. Similar to previous reports (20, 21), GluR1-S845A mutants, CP-AMPARs were absent from perisyn- bath application of PhTX (3 ␮M) did not alter AMPAR aptic locations mainly due to lysosomal degradation. This reg- responses measured extracellularly in the presence of 100 ␮M ulation was mimicked by acute desphosphorylation of the DL-APV (102 Ϯ 2.6% of baseline at 60 min post-PhTX, n ϭ 7) GluR1-S845 site in wild-type mice by NMDA application. Fur- (Fig. 1A). However, when synaptic responses were probed using thermore, long-term depression (LTD) was associated with a paired-pulses of 50 ms interstimulus interval (ISI), PhTX sig- reduction in perisynaptic CP-AMPAR levels. Our findings suggest nificantly depressed AMPAR responses (84 Ϯ 2.2% of baseline that GluR1-S845 is necessary for maintaining CP-AMPARs on the at 60 min post-PhTX, n ϭ 18; P Ͻ 0.016, paired t-test) (Fig. 1A) surface, especially at perisynaptic sites, and suggest that the without altering the paired-pulse ratio (baseline ϭ 1.74 Ϯ 0.04, regulation of these receptors is involved in synaptic plasticity. post-PhTX ϭ 1.78 Ϯ 0.05, n ϭ 18, P ϭ 0.14, paired t-test). These results suggest that paired-pulse (PP) stimulation reveals CP- excitatory synaptic transmission ͉ GluR1 homomer AMPARs unlike conventional single-pulse (SP) stimulation. To test whether this is due to activation of perisynaptic receptors, we examined the effect of PhTX on hippocampal slices treated with egulation of AMPA receptor (AMPAR) function is critical ␮ Rfor excitatory synaptic function in the brain (1). The 10 M TBOA, an inhibitor of glutamate transporters, which majority of synaptic AMPARs are impermeable to Ca2ϩ due allows spill-over of glutamate. In the presence of TBOA, PhTX to the presence of the GluR2 subunits, which undergo RNA caused a significant reduction in AMPAR synaptic responses with SP stimulation (83 Ϯ 4.4% of baseline at 60 min post-PhTX, editing at the Q/R site within the pore loop (2). Recent ϭ Ͻ evidence suggests that many forms of synaptic plasticity are n 8; P 0.005, paired t-test) (Fig. 1A), similar to when using associated with changes in the subunit composition of synaptic PP stimulation. AMPARs, especially at the level of regulating the GluR2 Because the polyamine sensitivity of CP-AMPARs is voltage- dependent (22, 23), an alternative explanation for the action of lacking CP-AMPARs (3). Several studies support the regula- NEUROSCIENCE tion of GluR2 as a mechanism for activity-dependent alter- TBOA is that it induces glutamate accumulation at synapses to enhance postsynaptic depolarization, which then permits the ations in synaptic AMPAR subunit composition. For example, detection of synaptic CP-AMPARs. To investigate this, we CP-AMPAR plasticity (CARP) in cerebellar stellate cells is performed whole-cell voltage clamp experiments using SP stim- associated with synaptic incorporation of GluR2-containing ulations. Bath application of TBOA while holding the cells at AMPARs dependent on interaction with Pick1 (4, 5). Simi- Ϫ70 mV significantly increased the AMPAR-EPSC amplitude larly, the appearance of CP-AMPARs at synapses by ischemia (130 Ϯ 13.0% of baseline at 15 min post-TBOA, n ϭ 11; P Ͻ (6) or cocaine injection (7) is dependent on GluR2-Pick1 0.003, paired t-test) (Fig. 1B ). This suggests that blocking interaction. However, the appearance of synaptic CP- 1 glutamate transporters recruit additional AMPARs, likely peri- AMPARs under various in vitro and in vivo synaptic plasticity synaptic as the decay time constant (␶) of AMPAR-EPSCs was paradigms is often associated with an increase in the GluR1 also increased (pre-TBOA: 7.6 Ϯ 0.32 ms; post-TBOA: 8.2 Ϯ subunit with little change in the GluR2 levels (8–12), impli- 0.34 ms; n ϭ 11, P Ͻ 0.02, paired t-test). After the responses cating a GluR1-dependent mechanism. stabilized in the presence of TBOA, we bath applied PhTX, Previously, we found that experience-dependent appearance of CP-AMPARs in visual cortex correlates with an increase in the phosphorylation of S845 on the GluR1 subunit (9). GluR1- Author contributions: K.H. and H.-K.L. designed research; K.H., L.S., L.W.C., and J.G. S845 is a substrate of protein kinase A (PKA) (13), which when performed research; R.L.H. contributed new reagents/analytic tools; K.H., L.S., and L.W.C. phosphorylated enhances channel mean open probability (14) analyzed data; and K.H. and H.-K.L. wrote the paper. and promotes synaptic trafficking of GluR1-containing AM- Conflict of interest statement: Under a licensing agreement between Millipore Corpora- PARs (15, 16), especially to extrasynaptic sites (16–18). To tion and The Johns Hopkins University, R.L.H. is entitled to a share of royalties received by the University on sales of products described in this article. R.L.H. is a paid consultant to examine whether GluR1-S845 phosphorylation plays a role in Millipore Corporation. regulating AMPAR subunit composition, we performed a series 1To whom correspondence may be addressed. E-mail: [email protected] or of experiments using a line of mutant mice specifically lacking [email protected]. the S845 site (GluR1-S845A mutants) (19). Here we provide This article contains supporting information online at www.pnas.org/cgi/content/full/ evidence supporting the hypothesis that S845 phosphorylation 0910338106/DCSupplemental. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0910338106 PNAS ͉ November 24, 2009 ͉ vol. 106 ͉ no. 47 ͉ 20033–20038 Downloaded by guest on September 29, 2021 our data support the idea that CP-AMPARs are located peri- A 140 PP 100 M DL-APV synaptically. 3 M PhTX GluR1-S845 Phosphorylation Plays a Role in Maintaining Perisynaptic 100 CP-AMPARs. Next we examined how CP-AMPARs are main- % FP % FP tained at perisynaptic sites. We previously found that the phos- SP SP +TBOA phorylation status of GluR1-S845 correlates with the appear- ance of CP-AMPARs at visual cortex synapses when rodents are 60 deprived of vision (9). GluR1-S845 is a PKA site (13), which -20 0 20 40 60 plays a critical role in bidirectional synaptic plasticity (25, 26). Time (min) One proposed mechanism is that phosphorylation of GluR1- B B S845 ‘‘primes’’ the AMPARs for synaptic delivery (16, 19), and 1 2 stabilizes surface AMPARs (18, 26–28). To test the hypothesis (1)+(2) (2)+(3) that GluR1-S845 phosphorylation is involved specifically in (2) stabilizing the CP-AMPARs at perisynaptic sites, we used a line 140 140 10 M TBOA - 70 mV of mutant mice lacking the GluR1-S845 site (GluR1-S845A 3 M PhTX (1) mutants) (19). (3) 100 100 We first examined whether CP-AMPARs are present at perisynaptic sites in the GluR1-S845A homozygous (HM) mice % EPSC % EPSC ϭ 10 M TBOA -70 mV with by probing the synapses using the PP stimulation (ISI 50 ms). 100 M DL-APV In contrast to wild-types (Fig. 1A), GluR1-S845A HM lacked 60 60 PhTX sensitivity of AMPAR responses (103 Ϯ 2.7% of baseline 200 200 at 60 min post-PhTX, n ϭ 8) (Fig. 2A). Phosphorylation of Ri 100 Ri 100 GluR1-S845 also regulates the mean open probability of AM- 40 40 PAR channels (14), which could have prevented the detection of Rs 10 Rs 10 perisynaptic CP-AMPARs in the mutants. To rule this out, we -5 0 5 10 15 -10 0 10 20 increased the current through AMPAR channels in the GluR1- Time (min) Time (min) S845A HM by removing AMPAR desensitization using cy- C D ␮ 140 140 clothiazide (CTZ) (29). Bath application of 50 M CTZ in- 3 M PhTX 3 M PhTX creased both the amplitude and the duration of AMPAR responses (Fig. 2A) resulting in about 1.6-fold increase in the 100 100 total charge transfer (measured as the integrated area of AM- PAR response). However, a subsequent application of 3 ␮M % EPSC -70 mV with % EPSC -40 mV with PhTX during PP stimulation failed to alter AMPAR responses 100 M DL-APV 100 M DL-APV in the mutants (Fig. 2A). This suggests that the absence of PhTX 60 60 sensitivity with PP stimulation in GluR1-S845A HM is unlikely 300 200 due to a reduction in channel open probability, and support a loss Ri Rs Ri 100 Rs Ri 100 of perisynaptic CP-AMPARs.
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