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Hook-up of GluA2, GRIP and liprin-α for cholinergic muscarinic receptor-dependent LTD in the hippocampus Wu, Long-Jun; Wang, Yu-Tian; Zhuo, Min Jun 17, 2009

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ralssBioMed CentMolecular BrainOpen AcceEditorialHook-up of GluA2, GRIP and liprin-α for cholinergic muscarinic receptor-dependent LTD in the hippocampusLong-Jun Wu1, Yu-Tian Wang2 and Min Zhuo*1,3Address: 1Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada, 2Brain Research Centre, University of British Columbia, Vancouver, V6T 1Z3, Canada and 3Department of Brain and Cognitive Sciences, Seoul National University, Seoul 151-746, KoreaEmail: Long-Jun Wu - longjun.wu@utoronto.ca; Yu-Tian Wang - ytwang@interchange.ubc.ca; Min Zhuo* - min.zhuo@utoronto.ca* Corresponding author    AbstractThe molecular mechanism underlying muscarinic acetylcholine receptor-dependent LTD (mAChR-LTD) in the hippocampus is less studied. In a recent study, a novel mechanism is described. Theinduction of mAChR-LTD required the activation of protein tyrosine phosphatase (PTP), and theexpression was mediated by AMPA receptor endocytosis via interactions between GluA2, GRIPand liprin-α. The hook-up of these proteins may result in the recruitment of leukocyte commonantigen-related receptor (LAR), a PTP that is known to be involved in AMPA receptor trafficking.Interestingly, the similar molecular interaction cannot be applied to mGluR-LTD, despite the factthat the same G-protein involved in LTD is activated by both mAChR and mGluR. This discoveryprovides key molecular insights for cholinergic dependent cognitive function, and mAChR-LTD canserve as a useful cellular model for studying the roles of cholinergic mechanism in learning andmemory.EditorialActivity-dependent changes in synaptic strength, such aslong-term potentiation (LTP) and long-term depression(LTD), are thought to be the cellular models of learning andmemory [1]. In the hippocampus, several mechanisticallydistinct forms of LTD have been reported. Two main formsof LTD (NMDA receptor (NMDAR)- and metabotropicglutamate receptor (mGluR)-dependent LTD), have beenintensively studied at hippocampal CA1 region and the sign-aling pathways underlying LTD have been established. Forexample, NMDAR-LTD can be induced by prolonged lowfrequency stimulation (LFS). The mechanisms underlyingNMDAR-LTD include activation of NMDA receptor, postsy-naptic Ca2+ elevation, and subsequent activation of proteinI mGluR agonist) application, and is dependent on the acti-vation of group I mGluR. Similar postsynaptic AMPA recep-tor endocytosis and possible presynaptic reduction ofglutamate release are thought to contribute to reducedresponses [2-6].Less attention has been paid to another form of LTD, onewhich is dependent on muscarinic acetylcholine receptors(mAChR). First described in the visual cortex, mAChR-LTDwas subsequently found in various brain regions, includingthe perirhinal cortex and hippocampus [7-11]. Cholinergicneurotransmission has been long implicated in memory andcognition [12] and thus mAChR-LTD is proposed to be crit-ical for cholinergic-related brain functions and disease. How-Published: 17 June 2009Molecular Brain 2009, 2:17 doi:10.1186/1756-6606-2-17Received: 26 May 2009Accepted: 17 June 2009This article is available from: http://www.molecularbrain.com/content/2/1/17© 2009 Wu et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 3(page number not for citation purposes)phosphatases. The AMPA receptor endocytosis is likelyimportant for the expression of the depression. mGluR-LTDcan be induced following paired-pulse LFS or DHPG (Groupever, the molecular mechanisms underlying mAChR-LTDremain largely unknown. Since mAChRs and mGluRs acti-vate similar signaling pathways involving the same G-pro-Molecular Brain 2009, 2:17 http://www.molecularbrain.com/content/2/1/17teins and isoforms of phospholipase C (PLC) [13], it isreasonable to expect that mAChR-LTD and mGluR-LTDshare similar molecular mechanisms. However, a recentstudy by Dickinson and colleagues [this issue, Dickinson etal., Molecular Brain] sheds new light on the molecular mech-anisms underlying mAChR-LTD in the hippocampus. Usingwhole-cell patch clamp recording in hippocampal CA1pyramidal neurons from 4–5 week-old young rats, theyfound that mAChR-LTD requires the activation of M1 recep-tors and protein tyrosine phosphatases (PTPs), which in turnresult in AMPA receptor internalization via interactionsbetween GluA2, GRIP and liprin-α. However, these samemolecular interactions are not required for mGluR-LTD inthe hippocampus.The major cholinergic innervations of the hippocampuscome from the medial septum [14]. Five different mus-carinic receptor subtypes (M1-5) have been identified, allof them are expressed in the hippocampus. Among them,M1, 3, 5 are coupled to the Gq/11 and phospholipase C(PLC) pathway, while M2 and 4 receptors negatively reg-ulate adenylyl cyclases [15]. In the hippocampal CA1region, mAChR-LTD has only recently been identified. Itis induced following application of the cholinergic mus-carinic receptor agonist, carbachol (CCh) to hippocampalslices [7,11]. Here Cho and colleagues demonstrate thatmAChR-LTD does not require the involvement of NMDAreceptors. Moreover, mAChR-LTD occurs independentlyof mGluRs. These findings support the argument thatmAchR-LTD represents a unique form of LTD within thehippocampus. Consistent with previous studies, M1receptors were found to contribute to the induction ofmAChR-LTD. This is demonstrated by the use of a selec-tive M1 receptor agonist 77-LH-28-1, and the antagonist,pirenzepine. The cholinergic M1 receptor is known to linkto Gq and the subsequent PLC signaling pathway, whichinduces Ca2+ release from intracellular Ca2+ store and acti-vation of PKC. To further test whether mAChR-LTD isCa2+- or PKC-dependent, cyclopiazonic acid (for Ca2+store depletion), BAPTA (Ca2+ chelator), Ro 32-0432(PKC inhibitor) and PKC19-31 (inhibitory peptide forPKC) were used and none was shown to affect mAChR-LTD, providing the strong evidence that mAchR-LTD mayemploy special signaling pathways. Postsynaptic applica-tion of GDPβ S, a G-protein inhibitor, abolished mAChR-LTD. Taken together, these results suggest that the induc-tion of mAChR-LTD is dependent on M1 receptors and aG-protein signaling mechanism, but not on a conven-tional Gq-coupled pathway.Protein phosphatases are known to contribute to hippoc-ampal LTD [6]. For example, serine/threonine proteinphosphatases PP1 and PP2B are required for NMDAR-roles in mAChR-LTD. By postsynaptic application ofphosphatase inhibitors, they found that PTP, but not ser-ine/threonine protein phosphatases, is required formAChR-LTD. In addition, they also found that proteinsynthesis is not required for mAChR-LTD. This result isquite surprising, since protein synthesis has been found tobe required for both mGluR-LTD and mAChR-LTD inother studies [7,10,18]. It has been reported that extracel-lular signal-regulated kinase (ERK) and mammalian targetof rapamycin (mTOR) translational activation pathwayscontribute to protein synthesis-dependent LTD [7,19].Because different results have been reported in term of therequirement of protein synthesis in LTD, it would worth-while in future studies to examine the roles of ERK andmTOR pathways in mAChR-LTD.How then is mAChR-LTD expressed? AMPA receptorendocytosis is the key expression mechanism for bothNMDAR-LTD and mGluR-LTD [3,6,20,21]. In a previousreport, the surface GluA1 internalization has beenobserved following CCh treatment in cultured hippocam-pal neurons [7]. To examine the expression mechanism ofmAChR-LTD, Dickinson et al. compared the cell surfaceand total expression level of GluA2 in control versus CCh-treated hippocampal slices. Following CCh treatmentthey observed a reduction in GluA2 expression on the cellsurface, while total expression levels of GluA2 remainedlargely unchanged. These results suggest a significantincrease in GluA2-containing AMPA receptor endocytosisfollowing LTD induction.A number of studies have revealed that AMPA receptor-interacting proteins such as NSF, AP2, GRIP, ABP, andPICK1 are critically involved in AMPA receptor traffickingrelated synaptic plasticity [3,20,22]. Most notably, GRIP/ABP and/or PICK1 are required for NMDAR-LTD in hip-pocampus, cerebellum and cortex, while PICK1 isrequired for mGluR-LTD in ventral tegmental area, cere-bellum and perirhinal cortex [3,22]. However, it is stillunknown which interacting proteins are involved inmAChR-LTD. To address this question, Dickinson et al.used peptide inhibitors to block either the interactionbetween GluA2 and PICK1 (pep2-EVKI), or betweenGluA2 and GRIP/ABP as well as PICK1 (pep2-SVKI). Theyfound that pep2-SVKI, but not pep2-EVKI, inhibitedmAChR-LTD, suggesting that GRIP rather than PICK1 isinvolved in mAChR-LTD. Interestingly, pep2-SVKI did notblock mGluR-LTD, which suggests that neither GRIP norPICK1 is involved. These findings indicate a differentmechanism is likely involved at the level of AMPA recep-tor trafficking between mGluR- and mAChR-LTD.To further examine the mechanisms by which GRIP mod-Page 2 of 3(page number not for citation purposes)LTD, while protein tyrosine phosphatase (PTP) is requiredfor mGluR-LTD [6,16,17]. Therefore, Dickinson and col-leagues set out to study whether these phosphatases playulates GluA2 trafficking and mAChR-LTD, they focusedon the GRIP interacting protein, Liprin-α, which candirectly interact with GRIP via its PDZ6 domain [23]. TheyMolecular Brain 2009, 2:17 http://www.molecularbrain.com/content/2/1/17found that disrupting the interaction between GRIP andliprin-α using a synthetic peptide selectively blockedmAChR-LTD but not mGluR-LTD and NMDAR-LTD.These results suggest that the GRIP-liprin-α interaction isspecifically required for mAChR-LTD. Liprin-α couldrecruit leukocyte common antigen-related receptors(LAR), a PTP known to be involved in AMPA receptor traf-ficking, axon guidance and neuronal development [24].One attractive hypothesis is that activation of LAR phos-phatase is triggered in mAChR-LTD via it's interactionwith the liprin-α-GRIP-GluA2 complex and the subse-quent tyrosine dephosphorylation of GluA2. GluA2 tyro-sine dephosphorylation results in the release of GluA2from GRIP and AMPA receptor endocytosis, therebyexpressing LTD. Indeed, in the present study, spectrumPTP inhibitors which can inhibit LAR phosphatase activityare effective in blocking mAChR-LTD. In addition, it hasbeen reported that disruption of GRIP-liprin interactions,or knockdown of LAR interfere with dendritic AMPAreceptor distribution [23,24].In summary, Dickinson et al. examined the detailedinduction and expression mechanisms of mAChR-LTD inhippocampal CA1 region. They nicely demonstrated thatcholinergic M1 receptors, G-protein signaling, PTP activityand GluA2 internalization are involved in mAChR-LTD.More importantly, their results reveal that the interactionof GluA2-GRIP-liprin-α is required for mAChR-LTD, themechanisms of which may require the recruitment of LAR,GluA2 tyrosine dephosphorylation, and thus AMPAreceptor endocytosis. The present study unveils a novelcellular mechanism for mAChR-LTD, which is differentfrom mGluR-LTD. Future studies are needed to addresshow the activation of M1 receptor leads to the recruitmentof LAR-liprin-α-GRIP-GluA2 pathway. In addition, geneknockout mice deficient of AMPA receptor subunits canbe used to evaluate/confirm the roles of these subunits inmAChR-LTD. Lastly, it would be valuable to identifywhether the mechanisms observed in the present studyare required for synaptically-induced mAChR-LTD in vivoand the pathophysiological relevance of heterosynapticmAChR-LTD in brains under disease conditions.AcknowledgementsSupported by grants from the EJLB-CIHR Michael Smith Chair in Neuro-sciences and Mental Health, Canada Research Chair, and World Class Uni-versity (WCU) program to M. Z. L.-J.W. is supported by postdoctoral fellowships from the Canadian Institutes of Health Research and Fragile × Research Foundation of Canada.References1. Bliss TV, Collingridge GL: A synaptic model of memory: long-term potentiation in the hippocampus.  Nature 1993,361:31-39.2. Toyoda H, Zhao MG, Zhuo M: NMDA receptor-dependent long-3. Collingridge GL, Isaac JT, Wang YT: Receptor trafficking and syn-aptic plasticity.  Nat Rev Neurosci 2004, 5:952-962.4. Shepherd JD, Huganir RL: The cell biology of synaptic plasticity:AMPA receptor trafficking.  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Massey PV, Bhabra G, Cho K, Brown MW, Bashir ZI: Activation ofmuscarinic receptors induces protein synthesis-dependentlong-lasting depression in the perirhinal cortex.  Eur J Neurosci2001, 14:145-152.11. Scheiderer CL, McCutchen E, Thacker EE, Kolasa K, Ward MK, Par-sons D, Harrell LE, Dobrunz LE, McMahon LL: Sympatheticsprouting drives hippocampal cholinergic reinnervation thatprevents loss of a muscarinic receptor-dependent long-termdepression at CA3-CA1 synapses.  J Neurosci 2006,26:3745-3756.12. Sarter M, Parikh V: Choline transporters, cholinergic transmis-sion and cognition.  Nat Rev Neurosci 2005, 6:48-56.13. Bashir ZI: On long-term depression induced by activation ofG-protein coupled receptors.  Neurosci Res 2003, 45:363-367.14. Bolam JP, Hanley JJ, Booth PA, Bevan MD: Synaptic organisationof the basal ganglia.  J Anat 2000, 196(Pt 4):527-542.15. Venter JC, Fraser CM, Kerlavage AR, Buck MA: Molecular biologyof adrenergic and muscarinic cholinergic receptors. A per-spective.  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