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GRIP1 Is Required for Homeostatic Regulation of AMPAR Trafficking

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GRIP1 Is Required for Homeostatic Regulation of AMPAR Trafficking GRIP1 is required for homeostatic regulation of AMPAR trafficking Han L. Tan, Bridget N. Queenan, and Richard L. Huganir1 Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205 Contributed by Richard L. Huganir, July 1, 2015 (sent for review June 16, 2015) Homeostatic plasticity is a negative feedback mechanism that stabilizes membrane trafficking, and synaptic targeting of AMPARs, and the neurons during periods of perturbed activity. The best-studied form regulation of this interaction is critical for neuronal develop- of homeostatic plasticity in the central nervous system is the scaling ment and several forms of synaptic plasticity (7, 19–23). Loss of of excitatory synapses. Postsynaptic AMPA-type glutamate receptors GRIP1/2 slows activity-dependent AMPAR recycling (24) and (AMPARs) can be inserted into synapses to compensate for neuronal blocks cerebellar long-term depression (LTD) expression (20). inactivity or removed to compensate for hyperactivity. However, the Though the PDZ domains of GRIP1 and GRIP2 are highly molecular mechanisms underlying the homeostatic regulation of conserved, some regions between these PDZ domains are variable. AMPARs remain elusive. Here, we show that the expression of GRIP1, For example, the KIF-5 binding region of GRIP1 (between PDZ6 a multi-PDZ (postsynaptic density 95/discs large/zona occludens) and PDZ7) is poorly homologous with GRIP2 (25). This di- domain AMPAR-binding protein, is bidirectionally altered by neuronal vergence suggests that GRIP1 and GRIP2 are not entirely re- activity. Furthermore, we observe a subcellular redistribution of GRIP1 dundant, such that GRIP1 harbors unique abilities to regulate and a change in the binding of GRIP1 to GluA2 during synaptic AMPAR trafficking through the interactions with motor pro- scaling. Using a combination of biochemical, genetic, and elec- teins. Indeed, GRIP1 plays a primary role in Hebbian plasticity trophysiological methods, we find that loss of GRIP1 blocks the like LTD, given that GRIP1 can completely rescue the LTD accumulation of surface AMPARs and the scaling up of synaptic deficits in the GRIP1/2 double knockout background, whereas strength that occur in response to chronic activity blockade. Collec- GRIP2 can only partially rescue (20). In stark contrast to the tively, our data point to an essential role of GRIP1-mediated AMPAR well-known function of GRIP1/2 in Hebbian plasticity, the role NEUROSCIENCE trafficking during inactivity-induced synaptic scaling. of GRIP1/2 in synaptic scaling has not been examined. Here, we tested whether GRIP1 participates in the homeo- synaptic scaling | postsynaptic density | glutamate receptor | PDZ domain static regulation of AMPARs. We found that GRIP1 expression is bidirectionally altered during synaptic scaling. Activity also ssociative, or Hebbian, synaptic plasticity is widely thought changes the subcellular distribution of GRIP1 and its association Ato underlie information storage (1). However, changes in with GluA2. Using a combination of biochemical, genetic, and synaptic strength through these learning processes are inherently electrophysiological methods, we observed that inactivity-induced destabilizing for neuronal networks. Homeostatic scaling is one synaptic scaling up is blocked in GRIP1 knockout neurons due elegant mechanism proposed to counterbalance the destabilizing to impaired trafficking of AMPARs, whereas scaling down dur- forces of associative plasticity and maintain neuronal activity at a ing elevated activity is intact. Overall, these findings reveal an set point (2, 3). Homeostatic scaling was first identified in cultured essential role of GRIP1 in inactivity-induced synaptic scaling by neocortical neurons, where a prolonged increase in neuronal ac- regulating synaptic targeting of AMPARs. tivity globally scaled down excitatory synaptic responses while a chronic blockade of activity scaled up the responses (4, 5). Results AMPA-type glutamate receptors (AMPARs) are the principle GRIP1 Expression Is Bidirectionally Regulated by Activity. We first postsynaptic ionotropic glutamate receptors that mediate fast ex- examined GRIP1 protein levels during synaptic scaling. Cultured citatory synaptic transmission in the central nervous system. rat cortical neurons were treated with bicuculline (to induce AMPARs are tetrameric assemblies of highly homologous subunits encoded by four different genes, GluA1–4 (5, 6). Perturbing net- Significance work activity induces compensatory changes in surface AMPARs to restore neuronal firing rates (5). Accordingly, the mechanisms of Homeostatic plasticity constrains neuronal networks, allowing homeostatic regulation of AMPARs are currently under intense the brain to maintain a dynamic equilibrium. Loss of homeo- scrutiny. AMPAR trafficking is highly dynamic and regulated by static plasticity disrupts normal brain function and has been binding partners and posttranslational modifications (5, 7) in- implicated in autism spectrum disorder. Much of homeostatic cluding phosphorylation (8, 9). AMPAR trafficking, binding, and regulation centers on synapses. In particular, excitatory AMPA- modification are highly subunit-specific. It has been shown that the type glutamate receptors (AMPARs) are moved in and out of GluA2 subunit, but not GluA1, is required for inactivity-induced synapses to recalibrate neuronal activity. AMPARs can be scaling, and the C-terminal domain is crucial (10). Many mole- inserted at the surface to compensate for inactivity or removed cules known to regulate AMPAR trafficking, including AKAP5, to compensate for hyperactivity. We found that GRIP1, an α β Arc, TNF , 3 integrins, PSD-95, and PICK1, are all involved in AMPAR-binding protein implicated in autism, regulates the – or required for synaptic scaling in neuronal cultures (11 16). homeostatic shuttling of AMPARs between cytoplasmic and However, a clear picture of molecular mechanisms underlying synaptic pools. Restoring GRIP1 regulation may therefore scaling still remains largely unknown. prove therapeutically useful in autism. Glutamate receptor interacting protein 1 (GRIP1) and its homolog GRIP2 are major scaffolding proteins for GluA2/3 Author contributions: H.L.T. and R.L.H. designed research; H.L.T. and B.N.Q. performed subunit containing AMPARs. GRIP1 and 2 each contain seven research; H.L.T. and B.N.Q. analyzed data; and H.L.T. and R.L.H. wrote the paper. postsynaptic density 95/discs large/zona occludens (PDZ) do- The authors declare no conflict of interest. mains and interact directly with GluA2/3 C-terminal domains 1To whom correspondence should be addressed. Email: [email protected]. through their fourth and fifth PDZ domains (17, 18). The in- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. teraction between GRIP1 and GluA2/3 regulates surface expression, 1073/pnas.1512786112/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1512786112 PNAS Early Edition | 1of6 Downloaded by guest on October 2, 2021 hyperactivity) or TTX (to induce inactivity) for 48 h, which has 150 ABGRIP1 KO C been shown to induce homeostatic scaling down or scaling up, (conditional) respectively (4, 26). We found that bicuculline treatment signifi- 100 * ** *** EGFP Cre-EGFP sGluA1 cantly increased, whereas TTX treatment significantly decreased, sGluA2 total GRIP1 protein levels (Fig. 1 A and B), suggesting that sGluA1 50 (% of WT) sGluA3 GRIP1 protein levels may be important in controlling synaptic sGluA2 Surface AMPARs Surface AMPARs 0 strength during homeostatic scaling. sGluA3 WT KO WT KO WT KO WT To test whether GRIP1/2 are involved in the scaling process, we GluA1 GluA2 GluA3 GRIP2 KO used GRIP1 and GRIP2 knockout mice. GRIP1 conventional GRIP1&2 KO knockout mice have an early embryonic lethal phenotype, but DE GRIP1 KO F 150 (conditional) GRIP2 knockout mice are viable (27, 28). We therefore used GluA1 GluA2 GluA3 −/− EGFP Cre-EGFP GRIP1 conditional knockout mice (GRIP1 ), GRIP2 conven- 100 *** ** ** * *** * tGluA1 −/− tional knockout mice (GRIP2 ), and double-knockout GRIP1 GRIP1 tGluA2 −/− conditional plus GRIP2 conventional mice (GRIP1/2 ). To 50 tGluA1 (% of WT) tGluA3 achieve conditional knockout of GRIP1 in cultured neurons, Surface AMPARs tGluA2 -tubulin 0 lentiviruses expressing Cre recombinase (EGFP-IRES-Cre) were tGluA3 introduced. As previously described (20), 7–10 d after EGFP- WT WT WT -tubulin WT IRES-Cre virus infection, GRIP1 protein could no longer be de- GRIP2 KO GRIP2 KO GRIP2 KO GRIP2 KO tected (Fig. 1 C and D). Therefore, we routinely infected cortical GRIP1&2 KO GRIP1&2 KO GRIP1&2 KO GRIP1&2 KO G H GluA1 GluA2 GluA3 neurons with lentiviruses at day in vitro (DIV) 3 and performed 150 150 experiments 8–10 d later. Complete loss of GRIP1 was confirmed ns ns ns ns ns ns by Western blot for each experiment. In both WT and GRIP2 100 100 knockout mouse neurons, GRIP1 was significantly increased or decreased after 48 h of bicuculline or TTX treatments, re- 50 50 (% of WT) (% of WT) D E AMPARs Total spectively (Fig. 1 and ). These data show that GRIP1 ex- AMPARs Total 0 0 pression is bidirectionally regulated during synaptic scaling in T T both WT and GRIP2 knockout neurons. WT KO WT KO WT KO W WT W GluA1 GluA2 GluA3 GRIP2 KO GRIP2 KO GRIP2 KO Loss of GRIP1 or GRIP2 Decreases Surface AMPARs. We first exam- GRIP1&2 KO GRIP1&2 KO GRIP1&2 KO ined the consequences of GRIP deletion on AMPAR surface or Fig. 2. Loss of GRIP decreases surface AMPAR expression. (A, C, E, and
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