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SorCS2 is required for social memory and trafficking of the NMDA receptor

Molecular Psychiatry volume 26, pages 927–940 (2021)Cite this article

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Abstract

Social memory processing requires functional CA2 neurons, however the specific mechanisms that regulate their activity are poorly understood. Here, we document that SorCS2, a member of the family of the Vps10 family of sorting receptors, is highly expressed in pyramidal neurons of CA2, as well as ventral CA1, a circuit implicated in social memory. SorCS2 specifically localizes to the postsynaptic density and endosomes within dendritic spines of CA2 neurons. We have discovered that SorCS2 is a selective regulator of NMDA receptor surface trafficking in hippocampal neurons, without altering AMPA receptor trafficking. In addition, SorCS2 regulates dendritic spine density in CA2 neurons where SorCS2 expression is enriched, but not in dorsal CA1 neurons, which normally express very low levels of this protein. To specifically test the role of SorCS2 in behavior, we generated a novel SorCS2-deficient mouse, and identify a significant social memory deficit, with no change in sociability, olfaction, anxiety, or several hippocampal-dependent behaviors. Mutations in sorCS2 have been associated with bipolar disease, schizophrenia, and attention deficient-hyperactivity disorder, and abnormalities in social memory are core components of these neuropsychiatric conditions. Thus, our findings provide a new mechanism for social memory formation, through regulating synaptic receptor trafficking in pyramidal neurons by SorCS2.

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Fig. 1: SorCS2 localization in adult hippocampus.
Fig. 2: SorCS2 is proteolytically processed, and characterization of sorCS2−/− mouse.
Fig. 3: SorCS2 regulates the cell surface levels of NMDAR subunits, but not the AMPAR, and the NR2B density on plasma membrane and synapses of CA2 dendrites.
Fig. 4: SorCS2 regulates dendritic spine density of CA2 pyramidal neurons.
Fig. 5: sorCS2−/− mice display deficits in social memory.

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References

  1. Hitti FL, Siegelbaum SA. The hippocampal CA2 region is essential for social memory. Nature. 2014;508:88–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Smith AS, Williams Avram SK, Cymerblit-Sabba A, Song J, Young WS. Targeted activation of the hippocampal CA2 area strongly enhances social memory. Mol Psychiatry. 2016;21:1137–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Meira T, Leroy F, Buss EW, Oliva A, Park J, Siegelbaum SA. A hippocampal circuit linking dorsal CA2 to ventral CA1 critical for social memory dynamics. Nat Commun. 2018;9:4163.

    PubMed  PubMed Central  Google Scholar 

  4. Dudek SM, Alexander GM, Farris S. Rediscovering area CA2: unique properties and functions. Nat Rev Neurosci. 2016;17:89–102.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Young WS, Li J, Wersinger SR, Palkovits M. The vasopressin 1b receptor is prominent in the hippocampal area CA2 where it is unaffected by restraint stress or adrenalectomy. Neuroscience. 2006;143:1031–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Hermey G. The Vps10p-domain receptor family. Cell Mol Life Sci. 2009;66:2677–89.

    CAS  PubMed  Google Scholar 

  7. Nykjaer A, Lee R, Teng KK, Jansen P, Madsen P, Nielsen MS, et al. Sortilin is essential for proNGF-induced neuronal cell death. Nature. 2004;427:843–8.

    CAS  PubMed  Google Scholar 

  8. Deinhardt K, Kim T, Spellman DS, Mains RE, Eipper BA, Neubert TA, et al. Neuronal growth cone retraction relies on proneurotrophin receptor signaling through Rac. Sci Signal. 2011;4:ra82.

    PubMed  PubMed Central  Google Scholar 

  9. Hermey G, Plath N, Hübner CA, Kuhl D, Schaller HC, Hermans-Borgmeyer I. The three sorCS genes are differentially expressed and regulated by synaptic activity. J Neurochem. 2004;88:1470–6.

    CAS  PubMed  Google Scholar 

  10. Grupe A, Li Y, Rowland C, Nowotny P, Hinrichs AL, Smemo S, et al. A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease. Am J Hum Genet. 2006;78:78–88.

    CAS  PubMed  Google Scholar 

  11. Christoforou A, McGhee KA, Morris SW, Thomson PA, Anderson S, McLean A, et al. Convergence of linkage, association and GWAS findings for a candidate region for bipolar disorder and schizophrenia on chromosome 4p. Mol Psychiatry. 2011;16:240–2.

    CAS  PubMed  Google Scholar 

  12. Lionel AC, Crosbie J, Barbosa N, Goodale T, Thiruvahindrapuram B, Rickaby J, et al. Rare copy number variation discovery and cross-disorder comparisons identify risk genes for ADHD. Sci Transl Med. 2011;3:95ra75.

    CAS  PubMed  Google Scholar 

  13. Reitz C, Tokuhiro S, Clark LN, Conrad C, Vonsattel JP, Hazrati LN, et al. SORCS1 alters amyloid precursor protein processing and variants may increase Alzheimer’s disease risk. Ann Neurol. 2011;69:47–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Li Z, Zheng M, Abdalla BA, Zhang Z, Xu Z, Ye Q, et al. Genome-wide association study of aggressive behaviour in chicken. Sci Rep. 2016;6:30981. https://doi.org/10.1038/srep30981.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Glerup S, Bolcho U, Mølgaard S, Bøggild S, Vaegter CB, Smith AH, et al. SorCS2 is required for BDNF-dependent plasticity in the hippocampus. Mol Psychiatry. 2016;21:1740–51.

    CAS  PubMed  Google Scholar 

  16. Savas JN, Ribeiro LF, Wierda KD, Wright R, DeNardo-Wilke LA, Rice HC, et al. The sorting receptor SorCS1 regulates trafficking of neurexin and AMPA receptors. Neuron. 2015;87:764–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Hermey G, Schmidt N, Bluhm B, Mensching D, Ostermann K, Rupp C, et al. SorCS1 variants and amyloid precursor protein (APP) are co-transported in neurons but only SorCS1c modulates anterograde APP transport. J Neurochem. 2015;135:60–75.

    CAS  PubMed  Google Scholar 

  18. Breiderhoff T, Christiansen GB, Pallesen LT, Vaegter C, Nykjaer A, Holm MM, et al. Sortilin-related receptor SORCS3 is a postsynaptic modulator of synaptic depression and fear extinction. PLoS ONE. 2013;8:e75006.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Milner TA, Waters EM, Robinson DC, Pierce JP. Degenerating processes identified by electron microscopic immunocytochemical methods. Methods Mol Biol. 2011;793:23–59.

    CAS  PubMed  Google Scholar 

  20. Paxinos G, Franklin KBJ. The mouse brain in stereotaxic coordinates. 2nd ed. Hong Kong: Academic Press; 1996.

  21. Marques-Lopes J, Lynch MK, Van Kempen TA, Waters EM, Wang G, Iadecola C, et al. Female protection from slow-pressor effects of angiotensin II involves prevention of ROS production independent of NMDA receptor trafficking in hypothalamic neurons expressing angiotensin 1A receptors. Synapse. 2015;69:148–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Peters A, Palay SL, Webster H deF. The fine structure of the nervous system: neurons and their supporting cells. 3rd ed. New York: Oxford University Press; 1991.

  23. Van Kempen TA, Narayan A, Waters EM, Marques-Lopes J, Iadecola C, Glass MJ, et al. Alterations in the subcellular distribution of NADPH oxidase p47(phox) in hypothalamic paraventricular neurons following slow-pressor angiotensin II hypertension in female mice with accelerated ovarian failure. J Comp Neurol. 2016;524:2251–65.

    PubMed  Google Scholar 

  24. Yang J, Harte-Hargrove LC, Siao CJ, Marinic T, Clarke R, Ma Q, et al. proBDNF negatively regulates neuronal remodeling, synaptic transmission, and synaptic plasticity in hippocampus. Cell Rep. 2014;7:796–806.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Kaidanovich-Beilin O, Lipina T, Vukobradovic I, Roder J, Woodgett JR. Assessment of social interaction behaviors. J Vis Exp. 2011;e2473. https://doi.org/10.3791/2473.

  26. DeVito LM, Konigsberg R, Lykken C, Sauvage M, Young WS 3rd, Eichenbaum H. Vasopressin 1b receptor knock-out impairs memory for temporal order. J Neurosci. 2009;29:2676–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Kogan JH, Frankland PW, Silva AJ. Long-term memory underlying hippocampus-dependent social recognition in mice. Hippocampus. 2000;10:47–56.

    CAS  Google Scholar 

  28. Ferguson JN, Young LJ, Hearn EF, Matzuk MM, Insel TR, Winslow JT. Social amnesia in mice lacking the oxytocin gene. Nat Genet. 2000;25:284–8.

    CAS  PubMed  Google Scholar 

  29. Yang M, Crawley JN. (2009) Simple behavioral assessment of mouse olfaction. Curr Protoc Neurosci. https://doi.org/10.1002/0471142301.

  30. Chen ZY, Jing D, Bath KG, Ieraci A, Khan T, Siao CJ, et al. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science. 2006;314:140–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Oetjen S, Mahlke C, Hermans-Borgmeyer I, Hermey G. Spatiotemporal expression analysis of the growth factor receptor SorCS3. J Comp Neurol. 2014;522:3386–402.

    CAS  PubMed  Google Scholar 

  32. Lein ES, Callaway EM, Albright TD, Gage FH. Redefining the boundaries of the hippocampal CA2 subfield in the mouse using gene expression and 3-dimensional reconstruction. J Comp Neurol. 2005;485:1–10.

    CAS  PubMed  Google Scholar 

  33. Hermey G, Sjøgaard SS, Petersen CM, Nykjaer A, Gliemann J. Tumour necrosis factor alpha-converting enzyme mediates ectodomain shedding of Vps10p-domain receptor family members. Biochem J. 2006;395:285–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Glerup S, Olsen D, Vaegter CB, Gustafsen C, Sjoegaard SS, Hermey G, et al. SorCS2 regulates dopaminergic wiring and is processed into an apoptotic two-chain receptor in peripheral glia. Neuron. 2014;82:1074–87.

    CAS  PubMed  Google Scholar 

  35. Jacobs S, Wei W, Wang D, Tsien JZ. Importance of the GluN2B carboxy-terminal domain for enhancement of social memories. Learn Mem. 2015;22:401–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Jacobs S, Tsien JZ. Adult forebrain NMDA receptors gate social motivation and social memory. Neurobiol Learn Mem. 2017;138:164–72.

    CAS  PubMed  Google Scholar 

  37. van Strien NM, Cappaert NL, Witter MP. The anatomy of memory: an interactive overview of the parahippocampal-hippocampal network. Nat Rev Neurosci. 2009;10:272–82.

    PubMed  Google Scholar 

  38. Nakashiba T, Young JZ, McHugh TJ, Buhl DL, Tonegawa S. Transgenic inhibition of synaptic transmission reveals role of CA3 output in hippocampal learning. Science. 2008;319:1260–4.

    CAS  PubMed  Google Scholar 

  39. Suh J, Rivest AJ, Nakashiba T, Tominaga T, Tonegawa S. Entorhinal cortex layer III input to the hippocampus is crucial for temporal association memory. Science. 2011;334:1415–20.

    CAS  PubMed  Google Scholar 

  40. Wersinger SR, Kelliher KR, Zufall F, Lolait SJ, O’Carroll AM, Young WS 3rd. Social motivation is reduced in vasopressin 1b receptor null mice despite normal performance in an olfactory discrimination task. Horm Behav. 2004;46:638–45.

    CAS  PubMed  Google Scholar 

  41. Pagani JH, Zhao M, Cui Z, Avram SK, Caruana DA, Dudek SM, et al. Role of the vasopressin 1b receptor in rodent aggressive behavior and synaptic plasticity in hippocampal area CA2. Mol Psychiatry. 2015;20:490–9.

    CAS  PubMed  Google Scholar 

  42. Choquet D, Triller A. The dynamic synapse. Neuron. 2013;80:691–703.

    CAS  PubMed  Google Scholar 

  43. Shepherd JD, Huganir RL. The cell biology of synaptic plasticity: AMPA receptor trafficking. Annu Rev Cell Dev Biol. 2007;23:613–43.

    CAS  PubMed  Google Scholar 

  44. Giza JI, Kim J, Meyer HC, Anastasia A, Dincheva I, Zheng CI, et al. The BDNF Val66Met prodomain disassembles dendritic spines altering fear extinction circuitry and behavior. Neuron. 2018;99:1356.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Hardingham GE, Fukunaga Y, Bading H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci. 2002;5:405–14.

    CAS  Google Scholar 

  46. Zhou M, Baudry M. Developmental changes in NMDA neurotoxicity reflect developmental changes in subunit composition of NMDA receptors. J Neurosci. 2006;26:2956–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Sanhueza M, Fernandez-Villalobos G, Stein IS,  Kasumova G,  Zhang P, Bayer KU, et al. Role of the CaMKII/NMDA receptor complex in the maintenance of synaptic strength. J Neurosci. 2011;31:9170–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Petralia RS, Al-Hallaq RA, Wenthold RJ. Trafficking and targeting of NMDA receptors. In: Van Dongen AM, editor. Biology of the NMDA receptor. Boca Raton, FL: CRC Press/Taylor & Francis; 2009.

  49. Bezprozvanny I. Calcium signaling and neurodegenerative diseases. Trends Mol Med. 2009;15:89–100.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Lane RF, Steele JW, Cai D, Ehrlich ME, Attie AD, Gandy S. Protein sorting motifs in the cytoplasmic tail of SorCS1 control generation of Alzheimer’s amyloid-β peptide. J Neurosci. 2013;33:7099–107.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Baum AE, Akula N, Cabanero M, Cardona I, Corona W, Klemens B, et al. A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. Mol Psychiatry. 2008;13:197–207.

    CAS  PubMed  Google Scholar 

  52. Alemany S, Ribasés M, Vilor-Tejedor N, Bustamante M, Sánchez-Mora C, Bosch R, et al. New suggestive genetic loci and biological pathways for attention function in adult attention deficit/hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet. 2015;168:459–70.

    CAS  PubMed  Google Scholar 

  53. Ross CA, Margolis RL, Reading SA, Pletnikov M, Coyle JT. Neurobiology of schizophrenia. Neuron. 2006;52:139–53.

    CAS  PubMed  Google Scholar 

  54. Martinowich K, Schloesser RJ, Manji HK. Bipolar disorder: from genes to behavior pathways. J Clin Invest. 2009;119:726–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Nakazawa T, Hashimoto R, Sakoori K, Sugaya Y, Tanimura A, Hashimotodani Y, et al. Emerging roles of ARHGAP33 in intracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders. Nat Commun. 2016;7:10594.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Palmisano R, Heimann P, Shaw C, Troakes C, Schmitt-John T, Bartsch JW. Endosomal accumulation of APP in wobbler motor neurons reflects impaired vesicle trafficking: Implications for human motor neuron disease. BMC Neurosci. 2011;12:24.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the members of the Hempstead and Lee Laboratories for helpful discussions and advice about the manuscript, and the Neuroanatomy EM Core facilities in the Feil Family Brain and Mind Research Institute for EM. We also thank Dr Jianhong Luo from Zhejiang University for providing the NMDAR 2A and 2B plasmids. This work was supported by NIH grants P01 HD023315 and NS064114 to BLH, NS052819 to FSL, and DA08259 to TM, Shaanxi Province Natural Science Basic Research Foundation of China (2019JM-051) and National Natural Science Foundation of China (81971275) to JY.

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  1. Joanna Giza

    Present address: Department of Science, Borough of Manhattan Community College, The City University of New York, 199 Chambers Street N699J, New York, NY, 10007, USA

Authors and Affiliations

  1. Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, 710004, PR China

    Jianmin Yang

  2. Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, NY, 10065, USA

    Jianmin Yang, Qian Ma, Tina Marinic & Barbara L. Hempstead

  3. Department of Psychiatry, Weill Cornell Medical College, New York, NY, 10065, USA

    Iva Dincheva, Joanna Giza, Deqiang Jing & Francis S. Lee

  4. Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA

    Teresa A. Milner

  5. Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA

    Teresa A. Milner

  6. Department of Pediatrics, Weill Cornell Medicine, New York, NY, 10065, USA

    Anjali Rajadhyaksha

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Yang, J., Ma, Q., Dincheva, I. et al. SorCS2 is required for social memory and trafficking of the NMDA receptor. Mol Psychiatry 26, 927–940 (2021). https://doi.org/10.1038/s41380-020-0650-7

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