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Persistent Synaptic Scaling Independent of AMPA Receptor Subunit Composition

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Persistent Synaptic Scaling Independent of AMPA Receptor Subunit Composition The Journal of Neuroscience, July 17, 2013 • 33(29):11763–11767 • 11763 Brief Communications Persistent Synaptic Scaling Independent of AMPA Receptor Subunit Composition Haider F. Altimimi and David Stellwagen Centre for Research in Neuroscience, Department of Neurology and Neurosurgery, The Research Institute of the McGill University Health Centre, Montreal, Quebec H3G 1A4, Canada Despite long-standing evidence that the specific intracellular domains of AMPA-type glutamate receptor (AMPAR) subunits are critical for trafficking, it has recently been demonstrated that there is no absolute requirement for any AMPAR subunit for the receptor insertion underlying LTP. It is unclear whether this holds true to other forms of plasticity. Homeostatic synaptic plasticity (HSP) is an important form of negative feedback that provides stability to neuronal networks, and results at least in part from the insertion of AMPARs into glutamatergic synapses following chronic reductions in neuronal activity. Similar to LTP, the GluA1 subunit has been suggested to be the requisite subunit for HSP-induced AMPAR insertion and acute treatment with signaling molecules that underlie some forms of HSP results in the preferential incorporation of GluA2-lacking receptors. However, knockdown experiments have instead implicated a re- quirement for the GluA2 subunit. Here we re-examined the requirement for specific AMPAR subunit during chronic tetrodotoxin- induced HSP using hippocampal cultures derived from AMPAR subunit knock-out mice. We observed HSP in cultures from GluA1 Ϫ/Ϫ, GluA2 Ϫ/Ϫ, and GluA2 Ϫ/Ϫ GluA3 Ϫ/Ϫ mice, and conclude that, as with LTP, there is no subunit requirement for HSP. Introduction crease in neuronal activity, such as in LTP (Hayashi et al., 2000; Plasticity of excitatory synaptic transmission is in large part me- Passafaro et al., 2001; Shi et al., 2001). GluA1 dominates GluA2 in diated by changes in the content of AMPA-type glutamate recep- trafficking according to this model, and is the key for activity- tors (AMPARs) in the postsynaptic plasma membrane (Kerchner dependent synaptic insertion (Passafaro et al., 2001; Shi et al., and Nicoll, 2008). Consequently, there has been intense investi- 2001). However, recent experiments demonstrate that no sub- gation into the regulation of AMPAR trafficking, primarily fo- unit, neither GluA1 nor GluA2, is required for synaptic incorpo- cused on the differential contribution of the various AMPAR ration of AMPARs or for LTP (Kim et al., 2005; Panicker et al., subunits. AMPARs are heteromultimers, comprised of the sub- 2008; Granger et al., 2013). This challenges the notion of subunit units GluA1-4. In the CA1 region of the hippocampus, AMPARs specificity for other forms of synaptic plasticity. are principally composed of GluA1-GluA2 heteromers, with a Homeostatic synaptic plasticity (HSP), or synaptic scaling, is smaller contribution of GluA2-GluA3 heteromers and GluA1 ho- an important form of plasticity that acts in opposition to stan- momers (Wenthold et al., 1996; Lu et al., 2009; Rozov et al., dard Hebbian plasticity (LTP and LTD) to normalize synaptic 2012). The divergent cytosolic C-terminal domains of the sub- drive (Turrigiano, 2012). Much like Hebbian plasticity, HSP is units contain binding motifs for a variety of interacting proteins thought to be mediated in a large part through changes in post- thought to contribute differentially to trafficking of AMPARs synaptic AMPAR content (Lee, 2012). Most work on HSP has (Shepherd and Huganir, 2007). Based on those differences in the focused on the scaling up of glutamatergic synapses, induced by C-terminal domains, a subunits-specificity rule for AMPAR traf- the chronic reduction of neuronal activity. Mechanistic insight ficking has emerged, which posits that AMPARs containing from these studies has suggested that GluA1, as in LTP, may play GluA2 are functionally incorporated into the synapse under basal the predominant role. Several forms of activity deprivation cause conditions, whereas those containing GluA1 are excluded from the preferential increase in surface expression of GluA1 (Thiaga- the synapse and are functionally incorporated only with an in- rajan et al., 2005; Sutton et al., 2006; Hou et al., 2008; Garcia- Bereguiain et al., 2013). Moreover, factors that have been shown Received March 13, 2013; revised May 23, 2013; accepted June 10, 2013. to be required for scaling up appear to target GluA1 for increased Author contributions: H.F.A. and D.S. designed research; H.F.A. and D.S. performed research; H.F.A. and D.S. surface expression (Stellwagen et al., 2005; Stellwagen and analyzed data; H.F.A. and D.S. wrote the paper. Malenka, 2006; Aoto et al., 2008). However, interfering with ThisworkwassupportedbytheCanadianInstitutesofHealthResearch,andtheNaturalSciencesandEngineering GluA1 trafficking only reduced the magnitude of scaling up in Research Council of Canada (D.S.) and the Heart and Stroke Foundation Canada (H.F.A.). We thank Virginie Biou for help with cultures, and R. Huganir for reagents. neocortical cultures, whereas RNAi-mediated knockdown of The authors declare no competing financial interests. GluA2 completely abrogated scaling up (Gainey et al., 2009). In Correspondence should be addressed to Dr David Stellwagen, Centre for Research in Neuroscience, The Research light of the recent data demonstrating that LTP does not require InstituteoftheMcGillUniversityHealthCentre,LivingstonHallRoomL7-217,1650CedarAvenue,Montre´al,Que´bec any specific AMPAR subunit and can be expressed in the absence H3G 1A4, Canada. E-mail: [email protected]. DOI:10.1523/JNEUROSCI.1102-13.2013 of AMPARs altogether (Granger et al., 2013), we have re- Copyright © 2013 the authors 0270-6474/13/3311763-05$15.00/0 examined the AMPAR subunit requirement in the hippocampal 11764 • J. Neurosci., July 17, 2013 • 33(29):11763–11767 Altimimi and Stellwagen • Synaptic Scaling Independent of AMPAR Composition homeostatic response to network inactiv- ity. Similar to LTP, we find no require- ment for any particular AMPAR subunit. Materials and Methods Animals and neuronal culture. All procedures were performed in accordance with the guide- lines of the Canadian Council for Animal Care and the Montreal General Hospital Animal Care Committee. Cultures were prepared from GluA1 Ϫ/Ϫ, GluA2 Ϫ/Ϫ, GluA3 Ϫ/Ϫ,or GluA2 Ϫ/Ϫ GluA3 Ϫ/Ϫ, and compared with wild-type C57BL/6 mice. Hippocampi were dissected in cold HBSS from newborn (P0–P1) pups of either sex, trypsinized (0.05% trypsin/ EDTA; Life Tech) for 15–20 min, triturated and seeded on coverslips precoated with poly- D-lysine (10 ␮g/ml; Sigma-Aldrich) in 24-well plates at 75–150 ϫ 10 3 cells per well. Cultures were maintained in neurobasal supplemented with 0.5 mM Glutamax and 2% v/v B27 (all from Life Tech). 5-Fluoro-2Ј-deoxyuridine: uridine (0.13:0.33 mg/ml; Sigma-Aldrich) was added between DIV4-6. Cultures were treated Figure 1. AMPAR surface trafficking in response to inactivity is independent of subunit identity. A, Example images of cell- Ϫ/Ϫ with 1 ␮M TTX (Alomone Labs) for 2 d before surface labeling of GluA2 in wild-type and GluA1 neurons, control or treated for 2 d with TTX. B, Summary data showing an Ϫ Ϫ testing at DIV12-15 or at DIV21. increase in AMPAR surface levels with 2 d TTX treatment over control in wild-type and GluA1 / cultures (p Ͻ 0.01, n ϭ 60 Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Surface-labeling of AMPARs and image images per condition). C, Example images of cell-surface labeling of GluA1 in GluA3 / , and GluA2 / GluA3 / neurons, analysis. AMPAR surface staining and image controlandtreatedfor2dwithTTX.D,SummarydatashowinganincreaseinAMPARsurfacelevelswithTTXtreatmentovercontrol Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ analysis were done essentially as described in GluA3 / (p Ͻ 0.01), and GluA2 / GluA3 / cultures (p Ͻ 0.001, n ϭ 30–61 images per condition). previously (Stellwagen et al., 2005). The anti- GluA1 antibody (1:1000; gift from R. Huganir, Results Johns Hopkins University, Baltimore, MD) was used on fixed, nonper- To address the question of AMPAR subunit requirement for meabilized cells. The anti-GluA2 antibody (5–10 ␮g/ml, clone 6C4, Mil- AMPAR insertion during chronic activity blockade, we treated lipore) was added to live cultures in conditioned medium for 15–20 min at 37°C, washed with aCSF (see below), and fixed in 2.5% paraformalde- dissociated hippocampal cultures from newborn mice with hyde/4% sucrose in aCSF. Cells were permeabilized with 0.1% Triton constitutive deletions in AMPAR subunits with TTX for a period X-100, and labeled for MAP2 (0.5 ␮g/ml, clone HM-2, GeneTex). Images of 2 d before testing between DIV12-15. For wild-type and Ϫ/Ϫ were acquired using wide-field fluorescence or confocal laser scanning GluA1 mice, we assessed the surface expression of AMPARs microscopy, using 63ϫ objective and identical laser power and exposure using an antibody against the N-terminus of GluA2 on nonper- settings for any given experiment. For analysis, the total area of AMPAR meabilized cells. As expected,2dofactivity blockade results in a immunostaining was selected by thresholding, and normalized to total significant increase in the surface expression of AMPARs in wild- dendritic area (selected by using either background fluorescence or cor- type (Fig. 1A,B; wild-type TTX-treated 128 Ϯ 7% of control, p Ͻ responding MAP2 signal). The percentage of dendritic area containing 0.01). Consistent with previous reports (Zamanillo et al., 1999; AMPARs was then compared between conditions. Lu et al., 2009), the surface expression of AMPARs on neurons Electrophysiology and mEPSC analysis. Patch-clamp recordings were from GluA1 Ϫ/Ϫ cultures was greatly reduced with respect to performed in aCSF (in mM: NaCl 135, KCl 3.5, CaCl 2, MgCl 1.3, 2 2 wild-type cultures (ϳ15% of wild-type surface levels). However, HEPES 10, D-glucose 20, pH adjusted to 7.3–7.4 with NaOH), supple- we still found thata2dTTXtreatment produced a comparable mented with TTX (0.5 ␮M), picrotoxin (100 ␮M), and D-APV (25 ␮M).
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