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Perineuronal Nets Restrict the Induction of Long-Term Depression in the Mouse Hippocampal CA1 Region

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Abstract

Long-term depression (LTD) of synaptic efficacy is widely regarded as a cellular basis of learning and memory. The magnitude of hippocampal CA1 LTD induced by low-frequency stimulation (LFS) declines with age, but the mechanisms involved remain poorly understood. Perineuronal nets (PNNs) are specialized extracellular matrix structures that function in dampening synaptic plasticity during postnatal development, suggesting that PNN formation may restrict LTD induction in the adult hippocampus. Here, we show that PNNs tightly enwrap a subpopulation of parvalbumin (PV) interneurons in the hippocampal CA1 region and enzymatic removal of PNNs with the chondroitinase ABC alters the excitatory/inhibitory synaptic balance toward more excitation and restores the ability of LFS to induce an N-methyl-D-aspartate receptor-dependent LTD at Schaffer collateral-CA1 synapses in slices from male adult mice. Early interference with depolarizing GABA with Na+-K+-2Cl− cotransporter inhibitor bumetanide impairs the maturation of PNNs and enhances LTD induction. These results provide novel insights into a previously unrecognized role for PNNs around PV interneurons in restricting long-term synaptic plasticity at excitatory synapses on hippocampal CA1 neurons in adulthood.

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References

  1. Malenka RC, Bear MF (2004) LTP and LTD: an embarrassment of riches. Neuron 44:5–21

    Article  CAS  Google Scholar 

  2. Kemp A, Manahan-Vaughan D (2007) Hippocampal long-term depression: master or minion in declarative memory processes? Trends Neurosci 30:111–118

    Article  CAS  PubMed  Google Scholar 

  3. Pinar C, Fontaine CJ, Triviño-Paredes J, Lottenberg CP, Gil-Mohapel J, Christie BR (2017) Revisiting the flip side: long-term depression of synaptic efficacy in the hippocampus. Neurosci Biobehav Rev 80:394–413

    Article  PubMed  Google Scholar 

  4. Abraham WC (1996) Induction of heterosynaptic and homosynaptic LTD in hippocampal sub-regions in vivo. J Physiol Paris 90:305–306

    Article  CAS  PubMed  Google Scholar 

  5. Massey PV, Bashir ZI (2007) Long-term depression: multiple forms and implications for brain function. Trends Neurosci 30:176–184

    Article  CAS  PubMed  Google Scholar 

  6. Dudek SM, Bear MF (1992) Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor blockade. Proc Natl Acad Sci U S A 89:4363–4367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mulkey RM, Herron CE, Malenka RC (1993) An essential role for protein phosphatases in hippocampal long-term depression. Science 261:1051–1055

    Article  CAS  PubMed  Google Scholar 

  8. Fujii S, Saito K, Miyakawa H, Ito K, Kato H (1991) Reversal of long-term potentiation (depotentiation) induced by tetanus stimulation of the input to CA1 neurons of guinea pig hippocampal slices. Brain Res 555:112–122

    Article  CAS  PubMed  Google Scholar 

  9. Dudek SM, Bear MF (1993) Bidirectional long-term modification of synaptic effectiveness in the adult and immature hippocampus. J Neurosci 13:2910–2918

    Article  CAS  PubMed  Google Scholar 

  10. Bashir ZI, Collingridge GL (1994) An investigation of depotentiation of long-term potentiation in the CA1 region of the hippocampus. Exp Brain Res 100:437–443

    Article  CAS  PubMed  Google Scholar 

  11. O'Dell TJ, Kandel ER (1994) Low-frequency stimulation erases LTP through an NMDA receptor-mediated activation of protein phosphatases. Learn Mem 1:129–139

    CAS  PubMed  Google Scholar 

  12. Mayford M, Wang J, Kandel ER, O'Dell TJ (1995) CaMKII regulates the frequency-response function of hippocampal synapses for the production of both LTD and LTP. Cell 81:891–904

    Article  CAS  PubMed  Google Scholar 

  13. Milner AJ, Cummings DM, Spencer JP, Murphy KP (2004) Bi-directional plasticity and age-dependent long-term depression at mouse CA3-CA1 hippocampal synapses. Neurosci Lett 367:1–5

    Article  CAS  PubMed  Google Scholar 

  14. Celio MR, Spreafico R, De Biasi S, Vitellaro-Zuccarello L (1998) Perineuronal nets: past and present. Trends Neurosci 21:510–515

    Article  CAS  PubMed  Google Scholar 

  15. Wang D, Fawcett J (2012) The perineuronal net and the control of CNS plasticity. Cell Tissue Res 349:147–160

    Article  PubMed  Google Scholar 

  16. Sorg BA, Berretta S, Blacktop JM, Fawcett JW, Kitagawa H, Kwok JC, Miquel M (2016) Casting a wide net: role of perineuronal nets in neural plasticity. J Neurosci 36:11459–11468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pizzorusso T, Medini P, Berardi N, Chierzi S, Fawcett JW, Maffei L (2002) Reactivation of ocular dominance plasticity in the adult visual cortex. Science 298:1248–1251

    Article  CAS  PubMed  Google Scholar 

  18. Barritt AW, Davies M, Marchand F, Hartley R, Grist J, Yip P, McMahon SB, Bradbury EJ (2006) Chondroitinase ABC promotes sprouting of intact and injured spinal systems after spinal cord injury. J Neurosci 26:10856–10867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Massey JM, Hubscher CH, Wagoner MR, Decker JA, Amps J, Silver J, Onifer SM (2006) Chondroitinase ABC digestion of the perineuronal net promotes functional collateral sprouting in the cuneate nucleus after cervical spinal cord injury. J Neurosci 26:4406–4414

    Article  CAS  PubMed  Google Scholar 

  20. Lensjø KK, Lepperød ME, Dick G, Hafting T, Fyhn M (2017) Removal of perineuronal nets unlocks juvenile plasticity through network mechanisms of decreased inhibition and increased gamma activity. J Neurosci 37:1269–1283

    Article  PubMed  PubMed Central  Google Scholar 

  21. Dityatev A, Brückner G, Dityateva G, Grosche J, Kleene R, Schachner M (2007) Activity-dependent formation and functions of chondroitin sulfate-rich extracellular matrix of perineuronal nets. Dev Neurobiol 67:570–588

    Article  CAS  PubMed  Google Scholar 

  22. Favuzzi E, Marques-Smith A, Deogracias R, Winterflood CM, Sánchez-Aguilera A, Mantoan L, Maeso P, Fernandes C et al (2017) Activity-dependent gating of parvalbumin interneuron function by the perineuronal net protein brevican. Neuron 95:639–655

    Article  CAS  PubMed  Google Scholar 

  23. Balmer TS (2016) Perineuronal nets enhance the excitability of fast-spiking neurons. eNeuro 3:e0112–e0116

    Article  Google Scholar 

  24. Gogolla N, Caroni P, Lüthi A, Herry C (2009) Perineuronal nets protect fear memories from erasure. Science 325:1258–1261

    Article  CAS  PubMed  Google Scholar 

  25. Bukalo O, Schachner M, Dityatev A (2001) Modification of extracellular matrix by enzymatic removal of chondroitin sulfate and by lack of tenascin-R differentially affects several forms of synaptic plasticity in the hippocampus. Neuroscience 104:359–369

    Article  CAS  PubMed  Google Scholar 

  26. Kochlamazashvili G, Henneberger C, Bukalo O, Dvoretskova E, Senkov O, Lievens PM, Westenbroek R, Engel AK et al (2010) The extracellular matrix molecule hyaluronic acid regulates hippocampal synaptic plasticity by modulating postsynaptic L-type Ca2+ channels. Neuron 67:116–128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Carstens KE, Phillips ML, Pozzo-Miller L, Weinberg RJ, Dudek SM (2006) Perineuronal nets suppress plasticity of excitatory synapses on CA2 pyramidal neurons. J Neurosci 36:6312–6320

    Article  CAS  Google Scholar 

  28. Ben-Ari Y, Holmes GL (2005) The multiple facets of γ-aminobutyric acid dysfunction in epilepsy. Curr Opin Neurol 18:141–145

    Article  CAS  PubMed  Google Scholar 

  29. Ben-Ari Y, Woodin MA, Sernagor E, Cancedda L, Vinay L, Rivera C, Legendre P, Luhmann HJ et al (2012) Refuting the challenges of the developmental shift of polarity of GABA actions: GABA more exciting than ever! Front Cell Neurosci 6:35

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Sernagor E, Chabrol F, Bony G, Cancedda L (2010) GABAergic control of neurite outgrowth and remodeling during development and adult neurogenesis: general rules and differences in diverse systems. Front Cell Neurosci 4:11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wang DD, Kriegstein AR (2011) Blocking early GABA depolarization with bumetanide results in permanent alterations in cortical circuits and sensorimotor gating deficits. Cereb Cortex 21:574–587

    Article  PubMed  Google Scholar 

  32. Deidda G, Parrini M, Naskar S, Bozarth IF, Contestabile A, Cancedda L (2015) Reversing excitatory GABAAR signaling restores synaptic plasticity and memory in a mouse model of Down syndrome. Nat Med 21:318–326

    Article  CAS  PubMed  Google Scholar 

  33. Yang CH, Huang CC, Hsu KS (2012) A critical role for protein tyrosine phosphatase nonreceptor type 5 in determining individual susceptibility to develop stress-related cognitive and morphological changes. J Neurosci 32:7550–7562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lin YT, Chen CC, Huang CC, Nishimori K, Hsu KS (2017) Oxytocin stimulates hippocampal neurogenesis via oxytocin receptor expressed in CA3 pyramidal neurons. Nat Commun 8:537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ueno H, Suemitsu S, Okamoto M, Matsumoto Y, Ishihara T (2017) Parvalbumin neurons and perineuronal nets in the mouse prefrontal cortex. Neuroscience 343:115–127

    Article  CAS  PubMed  Google Scholar 

  36. Huang CC, Hsu KS (2010) Activation of muscarinic acetylcholine receptors induces a nitric oxide-dependent long-term depression in rat medial prefrontal cortex. Cereb Cortex 20:982–996

    Article  PubMed  Google Scholar 

  37. Huang CC, Yeh CM, Wu MY, Chang AY, Chan JY, Chan SH, Hsu KS (2011) Cocaine withdrawal impairs metabotropic glutamate receptor-dependent long-term depression in the nucleus accumbens. J Neurosci 31:4194–4203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yamada J, Ohgomori T, Jinno S (2015) Perineuronal nets affect parvalbumin expression in GABAergic neurons of the mouse hippocampus. Eur J Neurosci 41:368–378

    Article  CAS  PubMed  Google Scholar 

  39. McRae PA, Baranov E, Sarode S, Brooks-Kayal AR, Porter BE (2010) Aggrecan expression, a component of the inhibitory interneuron perineuronal net, is altered following an early-life seizure. Neurobiol Dis 39:439–448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yamada J, Jinno S (2013) Spatio-temporal differences in perineuronal net expression in the mouse hippocampus, with reference to parvalbumin. Neuroscience 253:368–379

    Article  CAS  PubMed  Google Scholar 

  41. Kemp N, McQueen J, Faulkes S, Bashir ZI (2000) Different forms of LTD in the CA1 region of the hippocampus: role of age and stimulus protocol. Eur J Neurosci 12:360–366

    Article  CAS  PubMed  Google Scholar 

  42. Kwok JC, Dick G, Wang D, Fawcett JW (2011) Extracellular matrix and perineuronal nets in CNS repair. Dev Neurobiol 71:1073–1089

    Article  CAS  PubMed  Google Scholar 

  43. Lee HK, Kameyama K, Huganir RL, Bear MF (1998) NMDA induces long-term synaptic depression and dephosphorylation of the GluR1 subunit of AMPA receptors in hippocampus. Neuron 21:1151–1162

    Article  CAS  PubMed  Google Scholar 

  44. Dudek SM, Bear MF (1993) Bidirectional long-term modification of synaptic effectiveness in the adult and immature hippocampus. J Neurosci 13:2910–2918

    Article  CAS  PubMed  Google Scholar 

  45. Lee SH, Marchionni I, Bezaire M, Varga C, Danielson N, Lovett-Barron M, Losonczy A, Soltesz I (2014) Parvalbumin-positive basket cells differentiate among hippocampal pyramidal cells. Neuron 82:1129–1144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Horn ME, Nicoll RA (2018) Somatostatin and parvalbumin inhibitory synapses onto hippocampal pyramidal neurons are regulated by distinct mechanisms. Proc Natl Acad Sci U S A 115:589–594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wagner JJ, Alger BE (1995) GABAergic and developmental influences on homosynaptic LTD and depotentiation in rat hippocampus. J Neurosci 15:1577–1586

    Article  CAS  PubMed  Google Scholar 

  48. Norris CM, Korol DL, Foster TC (1996) Increased susceptibility to induction of long-term depression and long-term potentiation reversal during aging. J Neurosci 16:5382–5392

    Article  CAS  PubMed  Google Scholar 

  49. Foster TC, Kumar A (2007) Susceptibility to induction of long-term depression is associated with impaired memory in aged Fischer 344 rats. Neurobiol Learn Mem 87:522–535

    Article  PubMed  PubMed Central  Google Scholar 

  50. Sun ZY, Bozzelli PL, Caccavano A, Allen M, Balmuth J, Vicini S, Wu JY, Conant K (2018) Disruption of perineuronal nets increases the frequency of sharp wave ripple events. Hippocampus 28:42–52

    Article  CAS  PubMed  Google Scholar 

  51. Kerr DS, Abraham WC (1995) Cooperative interactions among afferents govern the induction of homosynaptic long-term depression in the hippocampus. Proc Natl Acad Sci U S A 92:11637–11641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Stevens CF, Tonegawa S, Wang Y (1994) The role of calcium-calmodulin kinase II in three forms of synaptic plasticity. Curr Biol 4:687–693

    Article  CAS  PubMed  Google Scholar 

  53. Kamal A, Ramakers GM, Urban IJ, De Graan PN, Gispen WH (1999) Chemical LTD in the CA1 field of the hippocampus from young and mature rats. Eur J Neurosci 11:3512–3516

    Article  CAS  PubMed  Google Scholar 

  54. Kumar A, Foster TC (2007) Shift in induction mechanisms underlies an age-dependent increase in DHPG-induced synaptic depression at CA3 CA1 synapses. J Neurophysiol 98:2729–2736

    Article  CAS  PubMed  Google Scholar 

  55. Palmer MJ, Irving AJ, Seabrook GR, Jane DE, Collingridge GL (1997) The group I mGlu receptor agonist DHPG induces a novel form of LTD in the CA1 region of the hippocampus. Neuropharmacology 36:1517–1532

    Article  CAS  PubMed  Google Scholar 

  56. Rohde M, Tokay T, Köhling R, Kirschstein T (2009) GABAA receptor inhibition does not affect mGluR-dependent LTD at hippocampal Schaffer collateral-CA1 synapses. Neurosci Lett 467:20–25

    Article  CAS  PubMed  Google Scholar 

  57. Paoletti P, Bellone C, Zhou Q (2013) NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci 14:383–400

    Article  CAS  PubMed  Google Scholar 

  58. Sans N, Petralia RS, Wang YX, Blahos J 2nd, Hell JW, Wenthold RJ (2000) A developmental change in NMDA receptor-associated proteins at hippocampal synapses. J Neurosci 20:1260–1271

    Article  CAS  PubMed  Google Scholar 

  59. Yashiro K, Philpot BD (2008) Regulation of NMDA receptor subunit expression and its implications for LTD, LTP, and metaplasticity. Neuropharmacology 55:1081–1094

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gray JA, Shi Y, Usui H, During MJ, Sakimura K, Nicoll RA (2011) Distinct modes of AMPA receptor suppression at developing synapses by GluN2A and GluN2B: single-cell NMDA receptor subunit deletion in vivo. Neuron 71:1085–1101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Bellone C, Nicoll RA (2007) Rapid bidirectional switching of synaptic NMDA receptors. Neuron 55:779–785

    Article  CAS  PubMed  Google Scholar 

  62. Fawcett JW (2015) The extracellular matrix in plasticity and regeneration after CNS injury and neurodegenerative disease. Prog Brain Res 218:213–226

    Article  PubMed  Google Scholar 

  63. Ahmadian G, Ju W, Liu L, Wyszynski M, Lee SH, Dunah AW, Taghibiglou C, Wang Y et al (2004) Tyrosine phosphorylation of GluR2 is required for insulin-stimulated AMPA receptor endocytosis and LTD. EMBO J 23:1040–1050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Liu L, Wong TP, Pozza MF, Lingenhoehl K, Wang Y, Sheng M, Auberson YP, Wang YT (2004) Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science 304:1021–1024

    Article  CAS  PubMed  Google Scholar 

  65. Nicholls RE, Alarcon JM, Malleret G, Carroll RC, Grody M, Vronskaya S, Kandel ER (2008) Transgenic mice lacking NMDAR-dependent LTD exhibit deficits in behavioral flexibility. Neuron 58:104–117

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the technical services provided by the Bio-image Core Facility of the National Core Facility Program for Biotechnology, Ministry of Science and Technology, Taiwan.

Funding

This work was supported by research grants from the National Health Research Institute (NHRI-EX107-10613NI) and the Ministry of Science and Technology (106-2320-B-006-026-MY3 and 107-2320-B-006-037-MY3), Taiwan.

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Authors and Affiliations

  1. Department of Pharmacology, College of Medicine, National Cheng Kung University, No. 1, University Rd., Tainan City, 70101, Taiwan

    Guan Hock Khoo, Yu-Ting Lin & Kuei-Sen Hsu

  2. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan

    Yu-Ting Lin, Tsung-Chih Tsai & Kuei-Sen Hsu

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  1. Guan Hock Khoo
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  2. Yu-Ting Lin
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Contributions

G.H.K., Y.T.L., T.C.T., and K.S.H. designed experiments. G.H.K., Y.T.L., and T.C.T. performed experiments and analyzed data. G.H.K., Y.T.L., and K.S.H. wrote the paper.

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Correspondence to Kuei-Sen Hsu.

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All experimental procedures were conducted in accordance with the National Institutes of Health guidelines for the care and use of laboratory animals and were approved by the Institutional Animal Care and Use Committee of National Cheng Kung University.

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Khoo, G.H., Lin, YT., Tsai, TC. et al. Perineuronal Nets Restrict the Induction of Long-Term Depression in the Mouse Hippocampal CA1 Region. Mol Neurobiol 56, 6436–6450 (2019). https://doi.org/10.1007/s12035-019-1526-1

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