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Targeted therapy of cognitive deficits in fragile X syndrome

Molecular Psychiatry volume 27, pages 2766–2776 (2022)Cite this article

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Abstract

Breaking an impasse in finding mechanism-based therapies of neuropsychiatric disorders requires a strategic shift towards alleviating individual symptoms. Here we present a symptom and circuit-specific approach to rescue deficits of reward learning in Fmr1 knockout mice, a model of Fragile X syndrome (FXS), the most common monogenetic cause of inherited mental disability and autism. We use high-throughput, ecologically-relevant automated tests of cognition and social behavior to assess effectiveness of the circuit-targeted injections of designer nanoparticles, loaded with TIMP metalloproteinase inhibitor 1 protein (TIMP-1). Further, to investigate the impact of our therapeutic strategy on neuronal plasticity we perform long-term potentiation recordings and high-resolution electron microscopy. We show that central amygdala-targeted delivery of TIMP-1 designer nanoparticles reverses impaired cognition in Fmr1 knockouts, while having no impact on deficits of social behavior, hence corroborating symptom-specificity of the proposed approach. Moreover, we elucidate the neural correlates of the highly specific behavioral rescue by showing that the applied therapeutic intervention restores functional synaptic plasticity and ultrastructure of neurons in the central amygdala. Thus, we present a targeted, symptom-specific and mechanism-based strategy to remedy cognitive deficits in Fragile X syndrome.

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Fig. 1: TIMP-1 release in the CeA rescues cognitive but not social deficits in Fmr1 KO mice.
Fig. 2: TIMP-1 release in the CeA normalizes impaired functional synaptic plasticity of Fmr1 KO mice.
Fig. 3: TIMP-1 release in the CeA normalizes synaptic morphology of Fmr1 KO mice.

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References

  1. Berry-Kravis EM, Lindemann L, Jønch AE, Apostol G, Bear MF, Carpenter RL, et al. Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome. Nat Rev Drug Disco. 2018;17:280–99.

    Article  CAS  Google Scholar 

  2. Bagni C, Tassone F, Neri G, Hagerman R. Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics. J Clin Invest. 2012;122:4314–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hessl D, Tassone F, Loesch DZ, Berry-Kravis E, Leehey MA, Gane LW, et al. Abnormal elevation of FMR1 mRNA is associated with psychological symptoms in individuals with the fragile X premutation. Am J Med Genet Part B Neuropsychiatr Genet Publ Int Soc Psychiatr Genet. 2005;139B:115–21.

    Article  CAS  Google Scholar 

  4. Hessl D, Grigsby J. Fragile X-associated tremor/ataxia syndrome: another phenotype of the fragile X gene. Clin Neuropsychol. 2016;30:810–4.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Schneider A, Johnston C, Tassone F, Sansone S, Hagerman RJ, Ferrer E, et al. Broad autism spectrum and obsessive-compulsive symptoms in adults with the fragile X premutation. Clin Neuropsychol. 2016;30:929–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. NIMH» Research Domain Criteria (RDoC). https://www.nimh.nih.gov/research/research-funded-by-nimh/rdoc/index.shtml. Accessed 13 October 2020.

  7. Janusz A, Milek J, Perycz M, Pacini L, Bagni C, Kaczmarek L, et al. The Fragile X mental retardation protein regulates matrix metalloproteinase 9 mRNA at synapses. J Neurosci J Soc Neurosci. 2013;33:18234–41.

    Article  CAS  Google Scholar 

  8. Dziembowska M, Milek J, Janusz A, Rejmak E, Romanowska E, Gorkiewicz T, et al. Activity-dependent local translation of matrix metalloproteinase-9. J Neurosci J Soc Neurosci. 2012;32:14538–47.

    Article  CAS  Google Scholar 

  9. Dziembowska M, Wlodarczyk J. MMP9: a novel function in synaptic plasticity. Int J Biochem Cell Biol. 2012;44:709–13.

    Article  CAS  PubMed  Google Scholar 

  10. Wójtowicz T, Mozrzymas JW. Matrix metalloprotease activity shapes the magnitude of EPSPs and spike plasticity within the hippocampal CA3 network. Hippocampus. 2014;24:135–53.

    Article  PubMed  CAS  Google Scholar 

  11. Jasińska M, Miłek J, Cymerman IA, Łęski S, Kaczmarek L, Dziembowska M. miR-132 Regulates Dendritic Spine Structure by Direct Targeting of Matrix Metalloproteinase 9 mRNA. Mol Neurobiol. 2015;53:1–12.

    Google Scholar 

  12. Vafadari B, Salamian A, Kaczmarek L. MMP-9 in translation: from molecule to brain physiology, pathology, and therapy. J Neurochem. 2016;139:91–114.

    Article  CAS  PubMed  Google Scholar 

  13. Beroun A, Mitra S, Michaluk P, Pijet B, Stefaniuk M, Kaczmarek L. MMPs in learning and memory and neuropsychiatric disorders. Cell Mol Life Sci CMLS. 2019;76:3207–28.

    Article  CAS  PubMed  Google Scholar 

  14. Bilousova TV, Rusakov DA, Ethell DW, Ethell IM. Matrix metalloproteinase-7 disrupts dendritic spines in hippocampal neurons through NMDA receptor activation. J Neurochem. 2006;97:44–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bilousova TV, Dansie L, Ngo M, Aye J, Charles JR, Ethell DW, et al. Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model. J Med Genet. 2009;46:94–102.

    Article  CAS  PubMed  Google Scholar 

  16. Castagnola S, Bardoni B, Maurin T. The Search for an Effective Therapy to Treat Fragile X Syndrome: Dream or Reality? Front Synaptic Neurosci. 2017;9:15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Wen TH, Binder DK, Ethell IM, Razak KA. The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders. Front Mol Neurosci. 2018;11:270.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Kokash J, Alderson EM, Reinhard SM, Crawford CA, Binder DK, Ethell IM, et al. Genetic reduction of MMP-9 in the Fmr1 KO mouse partially rescues prepulse inhibition of acoustic startle response. Brain Res. 2019;1719:24–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Toledo MA, Wen TH, Binder DK, Ethell IM, Razak KA. Reversal of ultrasonic vocalization deficits in a mouse model of Fragile X Syndrome with minocycline treatment or genetic reduction of MMP-9. Behav Brain Res. 2019;372:112068.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lovelace JW, Rais M, Palacios AR, Shuai XS, Bishay S, Popa O, et al. Deletion of Fmr1 from forebrain excitatory neurons triggers abnormal cellular, EEG, and behavioral phenotypes in the auditory cortex of a Mouse Model of Fragile X Syndrome. Cereb Cortex N. Y N. 1991. 2020;30:969–88.

    Google Scholar 

  21. Pirbhoy PS, Rais M, Lovelace JW, Woodard W, Razak KA, Binder DK, et al. Acute pharmacological inhibition of matrix metalloproteinase-9 activity during development restores perineuronal net formation and normalizes auditory processing in Fmr1 KO mice. J Neurochem. 2020. https://doi.org/10.1111/jnc.15037.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Sidhu H, Dansie LE, Hickmott PW, Ethell DW, Ethell IM. Genetic removal of matrix metalloproteinase 9 rescues the symptoms of Fragile X Syndrome in a Mouse Model. J Neurosci. 2014;34:9867–79.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Rotschafer SE, Trujillo MS, Dansie LE, Ethell IM, Razak KA. Minocycline treatment reverses ultrasonic vocalization production deficit in a mouse model of Fragile X Syndrome. Brain Res. 2012;1439:7–14.

    Article  CAS  PubMed  Google Scholar 

  24. Dansie LE, Phommahaxay K, Okusanya AG, Uwadia J, Huang M, Rotschafer SE, et al. Long-lasting effects of minocycline on behavior in young but not adult Fragile X mice. Neuroscience.2013;246:186–98.

    Article  CAS  PubMed  Google Scholar 

  25. Paribello C, Tao L, Folino A, Berry-Kravis E, Tranfaglia M, Ethell IM, et al. Open-label add-on treatment trial of minocycline in fragile X syndrome. BMC Neurol. 2010;10:91.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Dziembowska M, Pretto DI, Janusz A, Kaczmarek L, Leigh MJ, Gabriel N, et al. High MMP-9 activity levels in fragile X syndrome are lowered by minocycline. Am J Med Genet A. 2013;161A:1897–903.

    Article  PubMed  CAS  Google Scholar 

  27. Leigh MJS, Nguyen DV, Mu Y, Winarni TI, Schneider A, Chechi T, et al. A randomized double-blind, placebo-controlled trial of minocycline in children and adolescents with fragile x syndrome. J Dev Behav Pediatr JDBP. 2013;34:147–55.

    Article  PubMed  Google Scholar 

  28. Schneider A, Leigh MJ, Adams P, Nanakul R, Chechi T, Olichney J, et al. Electrocortical changes associated with minocycline treatment in fragile X syndrome. J Psychopharmacol Oxf Engl. 2013;27:956–63.

    Article  CAS  Google Scholar 

  29. Gough A, Chapman S, Wagstaff K, Emery P, Elias E. Minocycline induced autoimmune hepatitis and systemic lupus erythematosus-like syndrome. BMJ.1996;312:169–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lefebvre N, Forestier E, Farhi D, Mahsa MZ, Remy V, Lesens O, et al. Minocycline-induced hypersensitivity syndrome presenting with meningitis and brain edema: a case report. J Med Case Rep. 2007;1:22.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Ochsendorf F. Minocycline in Acne Vulgaris. Am J Clin Dermatol. 2010;11:327–41.

    Article  PubMed  Google Scholar 

  32. Wright JW, Harding JW. Contributions of matrix metalloproteinases to neural plasticity, habituation, associative learning and drug addiction. Neural Plast. 2009;2009:579382.

    Article  PubMed  CAS  Google Scholar 

  33. Chaturvedi M, Figiel I, Sreedhar B, Kaczmarek L. Neuroprotection from tissue inhibitor of metalloproteinase-1 and its nanoparticles. Neurochem Int. 2012;61:1065–71.

    Article  CAS  PubMed  Google Scholar 

  34. Chaturvedi M, Molino Y, Sreedhar B, Khrestchatisky M, Kaczmarek L. Tissue inhibitor of matrix metalloproteinases-1 loaded poly(lactic-co-glycolic acid) nanoparticles for delivery across the blood-brain barrier. Int J Nanomed. 2014;9:575–88.

    Article  Google Scholar 

  35. Nothnick WB, Soloway P, Curry TE. Assessment of the role of tissue inhibitor of metalloproteinase-1 (TIMP-1) during the periovulatory period in female mice lacking a functional TIMP-1 gene. Biol Reprod. 1997;56:1181–8.

    Article  CAS  PubMed  Google Scholar 

  36. Brew K, Dinakarpandian D, Nagase H. Tissue inhibitors of metalloproteinases: evolution, structure and function11Dedicated to Professor H. Neurath on the occasion of his 90th birthday. Biochim Biophys Acta BBA - Protein Struct Mol Enzymol. 2000;1477:267–83.

    Article  CAS  Google Scholar 

  37. Okulski P, Jay TM, Jaworski J, Duniec K, Dzwonek J, Konopacki FA, et al. TIMP-1 abolishes MMP-9-dependent long-lasting long-term potentiation in the prefrontal cortex. Biol Psychiatry. 2007;62:359–62.

    Article  CAS  PubMed  Google Scholar 

  38. Brew K, Nagase H. The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochim Biophys Acta BBA - Mol Cell Res. 2010;1803:55–71.

    Article  CAS  Google Scholar 

  39. Duan X, Chan C, Guo N, Han W, Weichselbaum RR, Lin W. Photodynamic therapy mediated by nontoxic core-shell nanoparticles synergizes with immune checkpoint blockade to elicit antitumor immunity and antimetastatic effect on breast cancer. J Am Chem Soc. 2016;138:16686–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Aghebati‐Maleki A, Dolati S, Ahmadi M, Baghbanzhadeh A, Asadi M, Fotouhi A, et al. Nanoparticles and cancer therapy: perspectives for application of nanoparticles in the treatment of cancers. J Cell Physiol. 2020;235:1962–72.

    Article  PubMed  CAS  Google Scholar 

  41. He C, Duan X, Guo N, Chan C, Poon C, Weichselbaum RR, et al. Core-shell nanoscale coordination polymers combine chemotherapy and photodynamic therapy to potentiate checkpoint blockade cancer immunotherapy. Nat Commun. 2016;7:12499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Castro F, Pinto ML, Pereira CL, Serre K, Barbosa MA, Vermaelen K, et al. Chitosan/γ-PGA nanoparticles-based immunotherapy as adjuvant to radiotherapy in breast cancer. Biomaterials. 2020;257:120218.

    Article  CAS  PubMed  Google Scholar 

  43. Serra P, Santamaria P. Nanoparticle-based autoimmune disease therapy. Clin Immunol. 2015;160:3–13.

    Article  CAS  PubMed  Google Scholar 

  44. Kishimoto TK, Maldonado RA. Nanoparticles for the induction of antigen-specific immunological tolerance. Front Immunol. 2018;9.

  45. Serra P, Santamaria P. Nanoparticle-based approaches to immune tolerance for the treatment of autoimmune diseases. Eur J Immunol. 2018;48:751–6.

    Article  CAS  PubMed  Google Scholar 

  46. Zampieri R, Brozzetti A, Pericolini E, Bartoloni E, Gabrielli E, Roselletti E, et al. Prevention and treatment of autoimmune diseases with plant virus nanoparticles. Sci Adv. 2020;6:eaaz0295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Knapska E, Lioudyno V, Kiryk A, Mikosz M, Górkiewicz T, Michaluk P, et al. Reward learning requires activity of matrix metalloproteinase-9 in the central amygdala. J Neurosci Off J Soc Neurosci. 2013;33:14591–14600.

    Article  CAS  Google Scholar 

  48. Kim J, Zhang X, Muralidhar S, LeBlanc SA, Tonegawa S. Basolateral to central amygdala neural circuits for appetitive behaviors. Neuron. 2017;93:1464–.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Murase S, Winkowski D, Liu J, Kanold PO, Quinlan EM. Homeostatic regulation of perisynaptic matrix metalloproteinase 9 (MMP9) activity in the amblyopic visual cortex. ELife. 2019;8:e52503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kiryk A, Mochol G, Filipkowski RK, Wawrzyniak M, Lioudyno V, Knapska E, et al. Cognitive abilities of Alzheimer’s disease transgenic mice are modulated by social context and circadian rhythm. Curr Alzheimer Res. 2011;8:883–92.

    Article  CAS  PubMed  Google Scholar 

  51. Puścian A, Łęski S, Kasprowicz G, Winiarski M, Borowska J, Nikolaev T, et al. Eco-HAB as a fully automated and ecologically relevant assessment of social impairments in mouse models of autism. ELife.2016;5:e19532.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Fiala JC. Reconstruct: a free editor for serial section microscopy. J Microsc. 2005;218:52–61.

    Article  CAS  PubMed  Google Scholar 

  53. Deerinck TJ, Bushong EA, Thor A, Ellisman MH. National Center for Microscopy and Imaging Research - NCMIR - National Center for Microscopy and Imaging Research. https://ncmir.ucsd.edu/sbem-protocol. Accessed 22 May 2018.

  54. Gkogkas CG, Khoutorsky A, Cao R, Jafarnejad SM, Prager-Khoutorsky M, Giannakas N, et al. Pharmacogenetic inhibition of eIF4E-dependent Mmp9 mRNA translation reverses fragile X syndrome-like phenotypes. Cell Rep. 2014;9:1742–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Lovelace JW, Wen TH, Reinhard S, Hsu MS, Sidhu H, Ethell IM, et al. Matrix metalloproteinase-9 deletion rescues auditory evoked potential habituation deficit in a mouse model of Fragile X Syndrome. Neurobiol Dis. 2016;89:126–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Gantois I, Khoutorsky A, Popic J, Aguilar-Valles A, Freemantle E, Cao R, et al. Metformin ameliorates core deficits in a mouse model of fragile X syndrome. Nat Med. 2017;23:674–7.

    Article  CAS  PubMed  Google Scholar 

  57. Wen TH, Afroz S, Reinhard SM, Palacios AR, Tapia K, Binder DK, et al. Genetic reduction of matrix metalloproteinase-9 promotes formation of perineuronal nets around parvalbumin-expressing interneurons and normalizes auditory cortex responses in developing Fmr1 Knock-Out Mice. Cereb Cortex N. Y N. 1991. 2018;28:3951–64.

    Google Scholar 

  58. Winiarski M, Borowska J, Wołyniak RM, Jędrzejewska-Szmek J, Kondrakiewicz L, Mankiewicz L, et al. Social learning about rewards – how information from others helps to adapt to changing environment. BioRxiv. 2021:2021.03.09.434563.

  59. Klohs J, Baeva N, Steinbrink J, Bourayou R, Boettcher C, Royl G, et al. In vivo near-infrared fluorescence imaging of matrix metalloproteinase activity after cerebral ischemia. J Cereb Blood Flow Metab. 2009;29:1284–92.

    Article  CAS  PubMed  Google Scholar 

  60. Jeong S-R, Park H-Y, Kim Y, Lee K-W. Methylglyoxal-derived advanced glycation end products induce matrix metalloproteinases through activation of ERK/JNK/NF-κB pathway in kidney proximal epithelial cells. Food Sci Biotechnol. 2019;29:675–82.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Takahashi C, Sheng Z, Horan TP, Kitayama H, Maki M, Hitomi K, et al. Regulation of matrix metalloproteinase-9 and inhibition of tumor invasion by the membrane-anchored glycoprotein RECK. Proc Natl Acad Sci. 1998;95:13221–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Puścian A, Lęski S, Górkiewicz T, Meyza K, Lipp H-P, Knapska E. A novel automated behavioral test battery assessing cognitive rigidity in two genetic mouse models of autism. Front Behav Neurosci. 2014;8:140.

    PubMed  PubMed Central  Google Scholar 

  63. Puścian A, Winiarski M, Łęski S, Charzewski L, Nikolaev T, Borowska J. et al. Chronic fluoxetine treatment impairs motivation and reward learning by affecting neuronal plasticity in the central amygdala. Br J Pharm. 2021;178:672–88.

    Article  CAS  Google Scholar 

  64. Puścian A, Winiarski M, Łęski S, Charzewski Ł, Nikolaev T, Borowska J, et al. Chronic fluoxetine treatment impairs motivation and reward learning by affecting neuronal plasticity in the central amygdala. Br J Pharm. 2020. https://doi.org/10.1111/bph.15319.

    Article  Google Scholar 

  65. Gorkiewicz T, Balcerzyk M, Kaczmarek L, Knapska E. Matrix metalloproteinase 9 (MMP-9) is indispensable for long term potentiation in the central and basal but not in the lateral nucleus of the amygdala. Front Cell Neurosci. 2015;9:73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Irwin SA, Galvez R, Greenough WT. Dendritic spine structural anomalies in fragile-X mental retardation syndrome. Cereb Cortex N. Y N. 1991. 2000;10:1038–44.

    CAS  Google Scholar 

  67. De Toma I, Manubens-Gil L, Ossowski S, Dierssen M. Where environment meets cognition: a focus on two developmental intellectual disability disorders. Neural Plast. 2016;2016:4235898.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Radwanska K, Medvedev NI, Pereira GS, Engmann O, Thiede N, Moraes MFD, et al. Mechanism for long-term memory formation when synaptic strengthening is impaired. Proc Natl Acad Sci USA. 2011;108:18471–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Barton AK, Shety T, Bondzio A, Einspanier R, Gehlen H. Metalloproteinases and their tissue inhibitors in comparison between different chronic pneumopathies in the horse. Mediators Inflamm. 2015;2015:569512.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Chen G, Ge D, Zhu B, Shi H, Ma Q. Upregulation of matrix metalloproteinase 9 (MMP9)/tissue inhibitor of metalloproteinase 1 (TIMP1) and MMP2/TIMP2 ratios may be involved in lipopolysaccharide-induced acute lung injury. J Int Med Res. 2020;48:0300060520919592.

    CAS  PubMed Central  Google Scholar 

  71. Hou C, Miao Y, Wang X, Chen C, Lin B, Hu Z. Expression of matrix metalloproteinases and tissue inhibitor of matrix metalloproteinases in the hair cycle. Exp Ther Med. 2016;12:231–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Sharov AA, Schroeder M, Sharova TY, Mardaryev AN, Peters EMJ, Tobin DJ, et al. Matrix Metalloproteinase-9 Is Involved in the Regulation of Hair Canal Formation. J Invest Dermatol. 2011;131:257–60.

    Article  CAS  PubMed  Google Scholar 

  73. Jackson HW, Defamie V, Waterhouse P, Khokha R. TIMPs: versatile extracellular regulators in cancer. Nat Rev Cancer. 2017;17:38–53.

    Article  CAS  PubMed  Google Scholar 

  74. Arpino V, Brock M, Gill SE. The role of TIMPs in regulation of extracellular matrix proteolysis. Matrix Biol. 2015;44–46:247–54.

    Article  PubMed  CAS  Google Scholar 

  75. Cabral-Pacheco GA, Garza-Veloz I, Castruita-De la Rosa C, Ramirez-Acuña JM, Perez-Romero BA, Guerrero-Rodriguez JF, et al. The Roles of Matrix Metalloproteinases and Their Inhibitors in Human Diseases. Int J Mol Sci. 2020;21:9739.

    Article  CAS  PubMed Central  Google Scholar 

  76. Wang X, Bozdagi O, Nikitczuk JS, Zhai ZW, Zhou Q, Huntley GW. Extracellular proteolysis by matrix metalloproteinase-9 drives dendritic spine enlargement and long-term potentiation coordinately. Proc Natl Acad Sci USA. 2008;105:19520–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Nagy V, Bozdagi O, Matynia A, Balcerzyk M, Okulski P, Dzwonek J, et al. Matrix metalloproteinase-9 is required for hippocampal late-phase long-term potentiation and memory. J Neurosci J Soc Neurosci. 2006;26:1923–34.

    Article  CAS  Google Scholar 

  78. Magnowska M, Gorkiewicz T, Suska A, Wawrzyniak M, Rutkowska-Wlodarczyk I, Kaczmarek L, et al. Transient ECM protease activity promotes synaptic plasticity. Sci Rep. 2016;6:27757.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Lebitko T, Dzik J, Jędrzejewska-Szmek J, Chaturvedi M, Jaworski T, Nikolaev T, et al. c-Fos-MMP-9 pathway in central amygdala mediates approach motivation but not reward consumption. BioRxiv. 2020:2020.04.17.044792.

  80. Stefaniuk M, Beroun A, Lebitko T, Markina O, Leski S, Meyza K, et al. Matrix Metalloproteinase-9 and synaptic plasticity in the Central Amygdala in control of alcohol-seeking behavior. Biol Psychiatry. 2017;81:907–17.

    Article  CAS  PubMed  Google Scholar 

  81. Booker SA, Domanski APF, Dando OR, Jackson AD, Isaac JTR, Hardingham GE, et al. Altered dendritic spine function and integration in a mouse model of fragile X syndrome. Nat Commun. 2019;10:4813.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Aziz W, Kraev I, Mizuno K, Kirby A, Fang T, Rupawala H, et al. Multi-input Synapses, but Not LTP-Strengthened synapses, correlate with hippocampal memory storage in aged mice. Curr Biol. 2019;29:3600–.e4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Giese KP, Aziz W, Kraev I, Stewart MG. Generation of multi-innervated dendritic spines as a novel mechanism of long-term memory formation. Neurobiol Learn Mem. 2015;124:48–51.

    Article  CAS  PubMed  Google Scholar 

  84. Andraka K, Kondrakiewicz K, Rojek-Sito K, Ziegart-Sadowska K, Meyza K, Nikolaev T, et al. Distinct circuits in rat central amygdala for defensive behaviors evoked by socially signaled imminent versus remote danger. Curr Biol. 2021. https://doi.org/10.1016/j.cub.2021.03.047.

    Article  PubMed  Google Scholar 

  85. Ding Q, Sethna F, Wang H. Behavioral analysis of male and female Fmr1 knockout mice on C57BL/6 background. Behav Brain Res. 2014;271:72–8.

    Article  CAS  PubMed  Google Scholar 

  86. Nolan SO, Reynolds CD, Smith GD, Holley AJ, Escobar B, Chandler MA, et al. Deletion of Fmr1 results in sex-specific changes in behavior. Brain Behav. 2017;7:e00800.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Shattuck PT, Durkin M, Maenner M, Newschaffer C, Mandell DS, Wiggins L, et al. Timing of identification among children with an autism spectrum disorder: findings from a population-based Surveillance Study. J Am Acad Child Adolesc Psychiatry. 2009;48:474–83.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Russell G, Steer C, Golding J. Social and demographic factors that influence the diagnosis of autistic spectrum disorders. Soc Psychiatry Psychiatr Epidemiol. 2011;46:1283–93.

    Article  PubMed  Google Scholar 

  89. Dworzynski K, Ronald A, Bolton P, Happé F. How different are girls and boys above and below the diagnostic threshold for autism spectrum disorders? J Am Acad Child Adolesc Psychiatry. 2012;51:788–97.

    Article  PubMed  Google Scholar 

  90. Duvekot J, Ende J, van der, Verhulst FC, Slappendel G, Daalen E, van, Maras A, et al. Factors influencing the probability of a diagnosis of autism spectrum disorder in girls versus boys. Autism. 2016; https://doi.org/10.1177/1362361316672178.

  91. Loomes R, Hull L, Mandy WPL. What Is the male-to-female ratio in autism spectrum disorder? A systematic review and meta-analysis. J Am Acad Child Adolesc Psychiatry. 2017;56:466–74.

    Article  PubMed  Google Scholar 

  92. Ratto AB, Kenworthy L, Yerys BE, Bascom J, Wieckowski AT, White SW, et al. What about the girls? Sex-based differences in autistic traits and adaptive skills. J Autism Dev Disord. 2018;48:1698–711.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Utari A, Chonchaiya W, Rivera SM, Schneider A, Hagerman RJ, Faradz SMH, et al. Side effects of minocycline treatment in patients with fragile X syndrome and exploration of outcome measures. Am J Intellect Dev Disabil. 2010;115:433–43.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Siller SS, Broadie K. Matrix metalloproteinases and minocycline: therapeutic avenues for fragile X syndrome. Neural Plast. 2012;2012:e124548.

    Article  CAS  Google Scholar 

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Acknowledgements

We are thankful to Thomas G. Custer and Katie Ferguson for the critical reading of the manuscript and to Svitlana Antoniuk for the invaluable technical support.

Funding

This work was supported by a grant from Switzerland through the Swiss Contribution to the enlarged European Union (PSPB-210/2010), European Research Council Starting Grant (H 415148), grants from the National Science Center (2013/08/W/NZ4/00691 and 2015/18/E/NZ4/00600), the Foundation for Polish Science (MAB/2018/10): The Nencki-European Molecular Biology Laboratory Center of Excellence for Neural Plasticity and Brain Disorders BRAINCITY project, carried out within the International Research Agendas program of the Foundation for Polish Science, supported by the European Union under the European Regional Development Fund, and a Foundation for Polish Science (FNP) Team grant (Team/2016-1/6 to KN and LK). MC was supported by “Mobilność Plus”, a fellowship from Polish Ministry of Science and Higher Education grant number 1291/MOB/IV/2015/0. JJC was supported by the National Science Center grant 2017/27/N/NZ1/01381.

Author information

Authors and Affiliations

  1. Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland

    A. Puścian, M. Winiarski, J. Borowska, S. Łęski, T. Górkiewicz, M. Chaturvedi, K. Nowicka, M. Wołyniak, T. Nikolaev, K. Meyza, L. Kaczmarek & E. Knapska

  2. Yale School of Medicine, Department of Neuroscience, New Haven, CT, USA

    A. Puścian

  3. Center of Excellence for Neural Plasticity and Brain Disorders: BRAINCITY, a Nencki-EMBL Partnership, Warsaw, Poland

    A. Puścian, K. Nowicka, L. Kaczmarek & E. Knapska

  4. Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Headington, Oxford, UK

    M. Chaturvedi

  5. Laboratory of Molecular Basis of Synaptic Plasticity, Centre of New Technologies, University of Warsaw, Warsaw, Poland

    J. J. Chmielewska & M. Dziembowska

  6. Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland

    J. J. Chmielewska

Authors
  1. A. Puścian
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  2. M. Winiarski
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  3. J. Borowska
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  4. S. Łęski
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  5. T. Górkiewicz
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  6. M. Chaturvedi
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  7. K. Nowicka
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  8. M. Wołyniak
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  9. J. J. Chmielewska
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  10. T. Nikolaev
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  11. K. Meyza
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  12. M. Dziembowska
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  13. L. Kaczmarek
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  14. E. Knapska
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Contributions

Concept and design: AP, EK. Data acquisition: AP, MW, JB, TG, MC, MW, JJC, TN, KM, MD. Analysis and interpretation of data: AP, MW, SŁ, TG, TN, KM, LK, EK. Drafting and revising the article: AP, KM, LK, EK.

Corresponding authors

Correspondence to A. Puścian or E. Knapska.

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The authors declare no competing interests.

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Puścian, A., Winiarski, M., Borowska, J. et al. Targeted therapy of cognitive deficits in fragile X syndrome. Mol Psychiatry 27, 2766–2776 (2022). https://doi.org/10.1038/s41380-022-01527-5

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  • DOI: https://doi.org/10.1038/s41380-022-01527-5

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