PDZ binding of TARPγ-8 controls synaptic transmission but not synaptic plasticity.
- Authors
- Sumioka, Akio; Brown, Travis E; Kato, Akihiko S; Bredt, David S; Kauer, Julie A; Tomita, Susumu
- Year
- 2011
- Journal
- Nature neuroscience
- PMID
- 22002768
- DOI
- 10.1038/nn.2952
- PMCID
- PMC3206644
The reduction in synaptic transmission and plasticity in mice lacking the hippocampus-enriched AMPA receptor (AMPAR) auxiliary subunit TARPγ-8 could be a result of a reduction in AMPAR expression or of the direct action of γ-8. We generated TARPγ-8Δ4 knock-in mice lacking the C-terminal PDZ ligand. We found that synaptic transmission and AMPARs were reduced in the mutant mice, but extrasynaptic AMPAR expression and long-term potentiation (LTP) were unaltered. Our findings suggest that there are distinct TARP-dependent mechanisms for synaptic transmission and LTP.
TARP©-8 PDZ binding is necessary for synaptic localization of AMPARs. (a) diagram of the synaptic AMPAR/TARP/PSD-95 complex. The PDZ ligand (–TTPV) is deleted. (b) The anti-©-8 antibody recognized ©-8 in both γ-8+/+ and γ-8Δ4/Δ4, whereas anti-TTPV antibody recognized ©-8 only in WT. Brain lysates were immunoprecipitated with normal rabbit IgG (control) or anti ©-8 antibody, followed by western blotting. All full and uncropped blots are shown in Supplementary Figure 7. (c) PSD-95 is not associated with ©-8⊗4 in vivo. PSD-95 was co-immunoprecipitated with ©-8 in γ-8+/+, but not in γ-8Δ4/Δ4 mice. (d) Protein levels of ©-8, GluA1, and GluA2/3 were somewhat decreased in hippocampi in a ©-8⊗4 gene dosage-dependent manner (n=4). (e, f) Protein levels of ©-8, GluA1, and GluA2/3 in the PSD fraction from hippocampus were reduced in γ-8Δ4/Δ4 mice, but not in the Triton X-100-solublized synaptosome fraction (Syn/Tx). In contrast, expression of ©-8, GluA1, and GluA2/3 in the Syn/Tx fraction was significantly reduced in γ-8−/− mice, but not in γ-8Δ4/Δ4 mice. (f) Protein levels were normalized to those from γ-8+/+ mice (n=4). Synaptophysin (Sph) was used as a non-PSD protein. All data are given as mean ± s.e.m.; * P < 0.05.
The ©-8 PDZ ligand modulates AMPAR-mediated basal transmission, but not LTP. (a) Ratio of AMPAR- to NMDAR-EPSCs is reduced by ~30% in CA1 pyramidal cells from γ-8Δ4/Δ4 slices (n=11) compared with those from γ-8+/+ slices (n=5). Representative examples of averaged EPSCs (AMPAR current=light trace; NMDAR current=dark trace). Calibration: 100 ms, 20 pA (+/+) and 16 pA (⊗4/⊗4). (b) Ratio of stimulus intensity (input) to the EPSP slope (output). Input-output was significantly reduced in slices from γ-8Δ4/Δ4 (n=6) compared to those from γ-8+/+ mice (n=10). * P < 0.05 paired t-test. (c) 100 nM AMPA-evoked whole cell currents are reduced by ~38% in γ-8Δ4/Δ4 (n=8) compared to γ-8+/+ mice (n=7). Inset, AMPA-evoked current from representative cells are shown. Calibration: 1 min, 50 pA. (d) Extracellular recordings of field EPSPs before and after tetanic stimulation of Schaffer collaterals (arrow). LTP was elicited in γ-8+/+ (open squares; n=6), γ-8Δ4/Δ4 (gray squares; n=10) and γ-8+/Δ4 slices (light gray squares; n=9) to a similar degree, but attenuated in γ-8−/−slices (black triangles; n=4). Inset, averaged fEPSPs before (dark trace) and during LTP (light trace). Calibration: 10 ms, 0.5 mV (+/+), 0.45 mV (⊗4/⊗4), 0.38 (+/⊗4) and 0.5 mV (−/−). (e) Whole-cell recordings from CA1 pyramidal cells before and after a pairing protocol (arrow). LTP was induced in slices from γ-8+/+ (n=5), γ-8+/Δ4 heterozygote (n=4) and γ-8Δ4/Δ4 homozygote mice (n=6). Inset, representative examples of averaged EPSCs recorded before and during LTP. Calibration: 20 ms, 200 pA (+/+), 160 pA (⊗4/ ⊗4) and 200 pA (+/⊗4). All data are given as mean ± s.e.m.; * P < 0.05.
| Name | Type |
|---|---|
| AMPAR | drug |
| AMPAR-evoked current local | phenotype |
| CA1 pyramidal cells local | anatomy |
| CACNG8 | gene |
| CACNG8KO local | variant |
| CACNG8Δ4 local | variant |
| Dlg4 | gene |
| GRIA1 | gene |
| GRIA2 | gene |
| GRIA3 | gene |
| hippocampus | anatomy |
| input-output local | phenotype |
| LTP | phenotype |
| NMDAR | drug |
| Schaffer collaterals | anatomy |
| Synaptophysin local | drug |
| Triton X-100 | drug |
| γ-8+/+ local | variant |
| γ-8−/− local | variant |
| γ-8+/+ mice local | cohort |
| γ-8−/− mice local | cohort |
| γ-8+/Δ4 local | variant |
| γ-8Δ4 local | variant |
| γ-8Δ4/Δ4 mice local | cohort |
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