Thrombospondin-1 (TSP-1) and Neuronal Plasticity: Implications in Down Syndrome
Main Article Content
Abstract
Down syndrome is the most common genetic cause of intellectual disability. Nevertheless, under certain stimulation processes, Down syndrome people can develop certain intellectual skills, suggesting an active mechanism of neuronal plasticity. Defects in both dendritic arborization and dendritic spines could affect neuronal plasticity and contribute to the degree of intellectual disability in people with Down syndrome. However, the cellular mechanisms involved in this process are unknown. Thrombospondin-1 (TSP-1) is an astrocyte-secreted protein involved in the development and maintenance of dendritic spines and synapses, which is altered in Down syndrome. Nonetheless, the role of TSP-1 in neuronal plasticity is not well characterized. In this study, we analyze whether TSP-1 is involved in neuronal microstructure changes induced by environmental enrichment, a model of experience-dependent neuronal plasticity. We found that the increase in dendritic spine density induced by environmental enrichment is associated with an increase in TSP-1 levels in the hippocampus of wild-type mice. The lack of TSP-1 in TSP-1-/- mice produce changes in the number and length of dendritic branches and a decrease in both, the number of intersections and density of dendritic spines. Exposure of TSP-1-/- mice to environmental enrichment did not affect the dendritic length and branching and number of intersections, but increased the density of dendritic spines significantly. These results suggest a role of TSP-1 as an important factor regulating brain microstructural plasticity, whose activity is reduced in Down syndrome.
Keywords:
thrombospondin-1 (TSP-1), dendritic spines, enriched environments, neuronal plasticity, Down syndrome
Article Details
How to Cite
GARCIA, Octavio; VILLEGAS-PIÑA, Jesús Antonio; VILLEGAS-PIÑA, Jesús Antonio.
Thrombospondin-1 (TSP-1) and Neuronal Plasticity: Implications in Down Syndrome.
Medical Research Archives, [S.l.], v. 10, n. 10, oct. 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3168>. Date accessed: 16 apr. 2024.
doi: https://doi.org/10.18103/mra.v10i10.3168.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Silverman W. Down syndrome: cognitive phenotype. Ment Retard Dev Disabil Res Rev. 2007; 13:228-236. doi: 10.1002/mrdd.20156
2. Arias-Trejo N, Barron-Martinez JB. Languaje skill in Down syndrome. In Auza Benavides A, Schwartz RG, ed. Language development and disorders in Spanish-speaking children. Springer; 2017: 329-341
3. Carlesimo GA, Marotta L, Vicari S. Long-term memory in mental retardation: evidence for a specific impairment in subjects with Down's syndrome Neuropsychol. 1997;35:71-79. doi: 10.1016/s0028-3932(96)00055-3
4. Chapman RS, Hesketh LJ. Behavioral phenotype of individuals with Down syndrome. Ment Retard Dev Disabil Res Rev. 2000;6:84-95. doi: 10.1002/1098-2779(2000)6:2<84::AID-MRDD2>3.0.CO;2-P
5. Angulo-Chavira AQ, García O, Arias-Trejo N. Pupil response and attention skills in Down syndrome. Res Dev Disabil. 2017;70:40-49. doi: 10.1016/j.ridd.2017.08.011
6. Vicari S. Motor development and neuropsychological patterns in persons with Down syndrome. Behav Genet. 2006;36:355-364. doi: 10.1007/s10519-006-9057-8
7. Dierssen M. Down syndrome: the brain in trisomic mode. Nat Rev Neurosci. 2012;13:844-858. doi: 10.1038/nrn3314
8. Ponroy Bally B, Murai KK. Astrocytes in Down Syndrome Across the Lifespan. Front Cell Neurosci. 2021;15:702685. doi: 10.3389/fncel.2021.702685.
9. Garcia O, Flores-Aguilar L. Astroglial and microglial pathology in Down syndrome: Focus on Alzheimer's disease. Front Cell Neurosci. 2022;16:987212. doi: 10.3389/fncel.2022.987212
10. Olmos-Serrano JL, Kang HJ, Tyler WA, et al. Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination. Neuron. 2016;89:1208-1222. doi: 10.1016/j.neuron.2016.01.042.
11. Nithianantharajah J, Hannan AJ. Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci. 2006;7:697-709. doi: 10.1038/nrn1970
12. Kempermann G. Environmental enrichment, new neurons and the neurobiology of individuality. Nat Rev Neurosci. 2019;20:235-245. doi: 10.1038/s41583-019-0120-x.
13. Hirase H, Shinohara Y. Transformation of cortical and hippocampal neural circuit by environmental enrichment. Neurosci. 2014;280:282-298. doi: 10.1016/j.neuroscience.2014.09.031
14. Moser MB, Trommald M, Egeland T, et al. Spatial training in a complex environment and isolation alter the spine distribution differently in rat CA1 pyramidal cells. J Comp Neurol. 1997;380(3):373-381. doi: 10.1002/(sici)1096-9861(19970414)380:3<373::aid-cne6>3.0.co;2-#
15. Sutherland R, Gibb R, Kolb B. The hippocampus makes a significant contribution to experience-dependent neocortical plasticity. Behav Brain Res. 2010;214:121-124. doi: 10.1016/j.bbr.2010.05.051.
16. Gelfo F, De Bartolo P, Giovine A, et al. Layer and regional effects of environmental enrichment on the pyramidal neuron morphology of the rat. Neurobiol Learn Mem. 2009;91:353-365.
17. Landers MS, Knott GW, Lipp HP, et al. Synapse formation in adult barrel cortex following naturalistic environmental enrichment. Neurosci. 2011;199:143-152. doi: 10.1016/j.neuroscience.2011.10.040.
18. Martin YB, Negredo P, Avendaño C. Experience-dependent plasticity in early stations of sensory processing in mature brains: effects of environmental enrichment on dendrite measures in trigeminal nuclei. Brain Struct Funct. 2022;227:865-879. doi: 10.1007/s00429-021-02424-3.
19. Hines S, Bennett F. Effectiveness of early interventions for children with Down syndrome. Ment Retard Dev Disabil Res Rev. 1996;2:96-101
20. Dierssen M, Benavides-Piccione R, Martínez-Cué C, et al. Alterations of neocortical pyramidal cell phenotype in the Ts65Dn mouse model of Down syndrome: effects of environmental enrichment. Cereb Cortex. 2003;13:758-764. doi:10.1093/cercor/13.7.758
21. De Giorgio A. The roles of motor activity and environmental enrichment in intellectual disability. Somatosens Mot Res. 2017;34:34-43. doi: 10.1080/08990220.2016.1278204
22. Kondo MA, Gray LJ, Pelka GJ, et al. Affective dysfunction in a mouse model of Rett syndrome: Therapeutic effects of environmental stimulation and physical activity. Dev Neurobiol. 2016;76:209-224. doi: 10.1002/dneu.22308
23. Downs J, Rodger J, Li C, et al. Environmental enrichment intervention for Rett syndrome: an individually randomised stepped wedge trial. Orphanet J Rare Dis. 2018;13:3. doi: 10.1186/s13023-017-0752-8.
24. Restivo L, Ferrari F, Passino E, et al. Enriched environment promotes behavioral and morphological recovery in a mouse model for the fragile X syndrome. Proc Natl Acad Sci USA. 2005;102:11557-11562. doi: 10.1073/pnas.0504984102
25. Winarni TI, Schneider A, Borodyanskara M, et al. Early intervention combined with targeted treatment promotes cognitive and behavioral improvements in young children with fragile X syndrome. Case Rep Genet. 2012;2012:280813. doi: 10.1155/2012/280813
26. Woo CC, Donnelly JH, Steinberg-Epstein R, et al. Environmental enrichment as a therapy for autism: A clinical trial replication and extension. Behav Neurosci. 2015;129:412-422. doi: 10.1037/bne0000068
27. Aronoff E, Hillyer R, Leon M. Environmental Enrichment Therapy for Autism: Outcomes with Increased Access. Neural Plast. 2016;2016:2734915. Epub. doi: 10.1155/2016/2734915
28. Yamaguchi H, Hara Y, Ago Y, et al. Environmental enrichment attenuates behavioral abnormalities in valproic acid-exposed autism model mice. Behav Brain Res. 2017;333:67-73. doi: 10.1016/j.bbr.2017.06.035.
29. Frese S, Petersen JA, Ligon-Auer M, et al. Exercise effects in Huntington disease. J Neurol. 2017;264:32-39. doi: 10.1007/s00415-016-8310-1.
30. Novati A, Nguyen HP, Schulze-Hentrich J. Environmental stimulation in Huntington disease patients and animal models. Neurobiol Dis. 2022;171:105725. doi: 10.1016/j.nbd.2022.105725.
31. Stazi M, Wirths O. Physical activity and cognitive stimulation ameliorate learning and motor deficits in a transgenic mouse model of Alzheimer's disease. Behav Brain Res. 2021;15:397:112951. doi: 10.1016/j.bbr.2020.112951
32. Lazarov O, Robinson J, Tang YP, et al. Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. Cell. 2005;120:701-713. doi: 10.1016/j.cell.2005.01.015
33. Pedrinolla A, Venturelli M, Fonte C, et al. Exercise Training on Locomotion in Patients with Alzheimer's Disease: A Feasibility Study. J Alzheimers Dis. 2018;61:1599-1609. doi: 10.3233/JAD-170625
34. Campelo CLC, Santos JR, Silva AF, et al. Exposure to an enriched environment facilitates motor recovery and prevents short-term memory impairment and reduction of striatal BDNF in a progressive pharmacological model of parkinsonism in mice. Behav Brain Res. 2017;328:138-148. doi: 10.1016/j.bbr.2017.04.028
35. Jadavji NM, Kolb B, Metz GA. Enriched environment improves motor function in intact and unilateral dopamine-depleted rats. Neurosci. 2006;140: 1127-1138. doi: 10.1016/j.neuroscience.2006.03.027
36. O'Shea KS, Liu LH, Dixit VM. Thrombospondin and a 140 kd fragment promote adhesion and neurite outgrowth from embryonic central and peripheral neurons and from PC12 cells. Neuron. 1991; 91:231-237. Doi: 10.1016/0896-6273(91)90261-w
37. Osterhout DJ, Frazier WA, Higgins D. Thrombospondin promotes process outgrowth in neurons from the peripheral and central nervous systems. Dev Biol. 1992;150:256-265. doi: 10.1016/0012-1606(92)90240-h
38. Yu K, Ge J, Summers JB, et al. TSP-1 secreted by bone marrow stromal cells contributes to retinal ganglion cell neurite outgrowth and survival. PLoS One. 2008;3:e2470. doi: 10.1371/journal.pone.0002470.
39. Pu Y, Meng K, Gu C, et al. Thrombospondin-1 modified bone marrow mesenchymal stem cells (BMSCs) promote neurite outgrowth and functional recovery in rats with spinal cord injury. Oncotarget. 2017;8:96276-96289. doi: 10.18632/oncotarget.22018.
40. DeFreitas MF, Yoshida CK, Frazier WA, et al. Identification of integrin alpha 3 beta 1 as a neuronal thrombospondin receptor mediating neurite outgrowth. Neuron. 1995;15:333-343. doi: 10.1016/0896-6273(95)90038-1
41. Lu Z, Kipnis J. Thrombospondin 1-a key astrocyte-derived neurogenic factor. FASEB J. 2010;24:1925-1934. doi: 10.1096/fj.09-150573
42. Christopherson KS, Ullian EM, Stokes CC, et al. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell. 2005;120:421-433. Doi : 10.1016/j.cell.2004.12.020
43. Eroglu C, Allen NJ, Susman MW, et al. Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell. 2009;139:380-392. doi: 10.1016/j.cell.2009.09.025
44. Xu J, Xiao N, Xia J. Thrombospondin 1 accelerates synaptogenesis in hippocampal neurons through neuroligin 1. Nat Neurosci. 2010;13:22-24. doi: 10.1038/nn.2459
45. Mendus D, Sundaresan S, Grillet N, et al. Thrombospondins 1 and 2 are important for afferent synapse formation and function in the inner ear. Eur J Neurosci. 2014;39:1256-1267. doi: 10.1111/ejn.12486
46. Garcia O, Torres M, Helguera P, et al. A role for thrombospondin-1 deficits in astrocyte-mediated spine and synaptic pathology in Down's syndrome. PLoS One. 2010;5:e14200. doi: 10.1371/journal.pone.0014200.
47. Cheng C, Lau SK, Doering LC. Astrocyte-secreted thrombospondin-1 modulates synapse and spine defects in the fragile X mouse model. Mol Brain. 2016;9:74. doi: 10.1186/s13041-016-0256-9
48. Torres MD, Garcia O, Tang C, et al. Dendritic spine pathology and thrombospondin-1 deficits in Down syndrome. Free Radic Biol Med. 2018;114:10-14. doi: 10.1016/j.freeradbiomed.2017.09.025
49. Bray ER, Yungher BJ, Levay K, et al. Thrombospondin-1 Mediates Axon Regeneration in Retinal Ganglion Cells. Neuron. 2019;103:642-657 doi: 10.1016/j.neuron.2019.05.044
50. Liauw J, Hoang S, Choi M, et al. Thrombospondins 1 and 2 are necessary for synaptic plasticity and functional recovery after stroke. J Cereb Blood Flow Metab. 2008;28:1722-1732. doi: 10.1038/jcbfm.2008.65
51. Mendus D, Rankin-Gee EK, Mustapha M, et al. Increased sensitivity to kindling in mice lacking TSP1 Neurosci. 2015;305:302-308. doi: 10.1016/j.neuroscience.2015.07.075.
52. Nagai J, Rajbhandari AK, Gangwani MR, et al. Hyperactivity with Disrupted Attention by Activation of an Astrocyte Synaptogenic Cue. Cell. 2019; 177(5):1280-1292. doi: 10.1016/j.cell.2019.03.019.
53. Sztainberg Y, Chen A. An environmental enrichment model for mice. Nat Protoc. 2010;5:1535-1539. doi: 10.1038/nprot.2010.114.
54. Helguera P, Pelsman A, Pigino G, et al. ets-2 promotes the activation of a mitochondrial death pathway in Down's syndrome neurons. J Neurosci. 2005;25:2295-2303. doi: 10.1523/JNEUROSCI.5107-04.2005
55. Barón-Mendoza I, Del Moral-Sánchez I, Martínez-Marcial M, et al. Dendritic complexity in prefrontal cortex and hippocampus of the autistic-like mice C58/J. Neurosci Lett. 2019;703:149-155. doi: 10.1016/j.neulet.2019.03.018
56. Langhammer CG, Previtera ML, Sweet ES, et al. Automated Sholl analysis of digitized neuronal morphology at multiple scales: Whole cell Sholl analysis versus Sholl analysis of arbor subregions. Cytometry A. 2010;77:1160-1168. doi: 10.1002/cyto.a.20954.
57. Orlowski D, Bjarkam CR. A simple reproducible and time saving method of semi-automatic dendrite spine density estimation compared to manual spine counting. J Neurosci Meth. 2012;208:128-133. doi: 10.1016/j.jneumeth.2012.05.009
58. Risher WC, Ustunkaya T, Singh Alvarado J, et al. Rapid Golgi analysis method for efficient and unbiased classification of dendritic spines. PLoS One. 2014;10;9(9):e107591. doi: 10.1371/journal.pone.0107591
59. Sultan F. Dissection of different areas from mouse hippocampus. Bio Protoc. 2013;3(21). pii: e955
60. Binley KE, Ng WS, Tribble JR, et al. Sholl analysis: a quantitative comparison of semi-automated methods. J Neurosci Meth. 2014;225: 65-70. doi: 10.1016/j.jneumeth.2014.01.017
61. Zhao C, Isenberg JS, Popel AS. Human expression patterns: qualitative and quantitative analysis of thrombospondin-1 under physiological and pathological conditions. J Cell Mol Med. 2018;22:2086-2097. doi: 10.1111/jcmm.13565
62. Asch AS, Leung LL, Shapiro J, et al. Human brain glial cells synthesize thrombospondin. Proc Natl Acad Sci USA. 1986; 83:2904-2908. doi: 10.1073/pnas.83.9.2904
63. Iruela-Arispe ML, Liska DJ, Sage EH, et al. Differential expression of thrombospondin 1, 2, and 3 during murine development. Dev Dyn. 1993;197:40-56. doi: 10.1002/aja.1001970105
64. Buée L, Hof PR, Roberts DD, et al. Immunohistochemical identification of thrombospondin in normal human brain and in Alzheimer's disease. Am J Pathol. 1992;141:783-788.
65. Dierssen M, Ramakers GJ. Dendritic pathology in mental retardation: from molecular genetic to neurobiology. Genes Brain Behav. 2006;5 Suppl 2:48-60. Doi: 10.1111/j.1601-183X.2006.00224.x
66. Nishiwaki T, Yamaguchi T, Zhao C, et al. Reduced expression of thrombospondins and craniofacial dysmorphism in mice overexpressing Fra1. J Bone Miner Res. 2006; 21: 596–604 doi: 10.1359/jbmr.051216
67. Antonarakis SE, Skotko BG, Rafii MS, et al. Down syndrome. Nat Rev Dis Primers. 2020; 6;6(1):9. doi: 10.1038/s41572-019-0143-7.
68. Faherty CJ, Kerley D, Smeyne RJ. A Golgi-Cox morphological analysis of neuronal changes induced by environmental enrichment. Brain Res Dev Brain Res. 2003;141:55-61. doi: 10.1016/s0165-3806(02)00642-9
69. Kolb B, Gorny G, Soderpalm AH, et al. Environmental complexity has different effects on the structure of neurons in the prefrontal cortex versus the parietal cortex or nucleus accumbens. Synapse. 2003;48(3): 149-153. doi: 10.1002/syn.10196
70. Bose M, Munoz-Llancao P, Roychowdhury S, et al. Effect of the environment on the dendritic morphology of the rat auditory cortex. Synapse. 2010;64:97-110. doi: 10.1002/syn.20710
71. Rampon C, Jiang CH, Dong H, et al. Effects of environmental enrichment on gene expression in the brain. Proc Natl Acad Sci USA. 2000;97:12880-12884. doi: 10.1073/pnas.97.23.12880
72. Malik R, Chattarji S. Enhanced intrinsic excitability and EPSP-spike coupling accompany enriched environment-induced facilitation of LTP in hippocampal CA1 pyramidal neurons. J Neurophysiol. 2012;107:1366-1378. doi: 10.1152/jn.01009.2011
73. Bindu B, Alladi PA, Mansooralikhan BM, et al. Short-term exposure to an enriched environment enhances dendritic branching but not brain-derived neurotrophic factor expression in the hippocampus of rats with ventral subicular lesions. Neurosci. 2007;144:412-423. doi: 10.1016/j.neuroscience.2006.09.057
74. Lushnikova I, Skibo G, Muller D, et al. Synaptic potentiation induces increased glial coverage of excitatory synapses in CA1 hippocampus. Hippocampus. 2009;19:753-762. doi: 10.1002/hipo.20551
75. Zhao M, Choi YS, Obrietan K, et al. Synaptic plasticity (and the lack thereof) in hippocampal CA2 neurons. J Neurosci. 2007;27:12025-12032. doi: 10.1523/JNEUROSCI.4094-07.2007
76. Simons SB, Escobedo Y, Yasuda R, et al. Regional differences in hippocampal calcium handling provide a cellular mechanism for limiting plasticity. Proc Natl Acad Sci USA. 2009;106:14080-14084. doi: 10.1073/pnas.0904775106.
77. Kohara K, Pignatelli M, Rivest AJ, et al. Cell type-specific genetic and optogenetic tools reveal hippocampal CA2 circuits. Nat Neurosci. 2014;17: 269-279. doi: 10.1073/pnas.0904775106
78. Dudek SM, Alexander GM, Farris S. Rediscovering area CA2: unique properties and functions. Nat Rev Neurosci. 2016;17:89-102. doi: 10.1038/nrn.2015.22
79. Hitti FL, Siegelbaum SA. The hippocampal CA2 region is essential for social memory. Nature. 2014;508(7494): 88-92. Doi: 10.1038/nrn.2015.22
80. Stevenson EL, Caldwell HK. Lesions to the CA2 region of the hippocampus impair social memory in mice. Eur J Neurosci. 2014;40(9): 3294-3301. doi: 10.1111/ejn.12689
81. Pennington BF, Moon J, Edgin J, et al. The neuropsychology of Down syndrome: evidence for hippocampal dysfunction. Child Dev. 2003;74:75-93. Doi: 10.1111/1467-8624.00522
82. Powers BE, Santiago NA, Strupp BJ. Rapid forgetting of social learning in the Ts65Dn mouse model of Down syndrome: New evidence for hippocampal dysfunction. Behav Neurosci. 2018;132:51-56. doi: 10.1037/bne0000227
83. Redila VA, Christie BR. Exercise-induced changes in dendritic structure and complexity in the adult hippocampal dentate gyrus. Neurosci. 2006;137:1299-1307. doi: 10.1016/j.neuroscience.2005.10.050
84. Tashiro A, Makino H, Gage FH. Experience-specific functional modification of the dentate gyrus through adult neurogenesis: a critical period during an immature stage. J Neurosci. 2007;27:3252-3259. Doi: 10.1523/JNEUROSCI.4941-06.2007
85. Pereira AC, Huddleston DE, Brickman AM, et al. An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci USA. 2007;104:5638-5643. doi: 10.1073/pnas.0611721104
86. Eadie BD, Redila VA, Christie BR. Voluntary exercise alters the cytoarchitecture of the adult dentate gyrus by increasing cellular proliferation, dendritic complexity, and spine density. J Comp Neurol. 2005;486:39-47. doi: 10.1002/cne.20493
87. Gallitano AL, Satvat E, Gil M, et al. Distinct dendritic morphology across the blades of the rodent dentate gyrus. Synapse. 2016;70:277-282. doi: 10.1002/syn.21900.
88. Chakrabarti L, Scafidi J, Gallo V, et al. Environmental enrichment rescues postnatal neurogenesis defect in the male and female Ts65Dn mouse model of Down syndrome. Dev Neurosci. 2011;33:428-441. doi: 10.1159/000329423.
89. Perry VH, Maffei L. Dendritic competition: competition for what? Brain Res. 1988;469:195-208. doi: 10.1016/0165-3806(88)90182-4
90. McAllister, AK. Cellular and molecular mechanisms of dendrite growth. Cereb Cortex. 2000;10: 963-973. doi: 10.1093/cercor/10.10.963
91. Takashima S, Becker LE, Armstrong DL, et al. Abnormal neuronal development in the visual cortex of the human fetus and infant with down's syndrome. A quantitative and qualitative Golgi study. Brain Res. 1981;225:1-21. doi: 10.1016/0006-8993(81)90314-0
92. Villarroya O, Ballestín R, López-Hidalgo R, et al. Morphological alterations in the hippocampus of the Ts65Dn mouse model for Down Syndrome correlate with structural plasticity markers. Histol Histopathol. 2018;33:101-115. doi: 10.14670/HH-11-894
93. Becker LE, Armstrong DL, Chan F. Dendritic atrophy in children with Down's syndrome. Ann Neurol. 1986;20:520-526. doi: 10.1002/ana.410200413
94. Jung CK, Herms J. Structural dynamics of dendritic spines are influenced by an environmental enrichment: an in vivo imaging study. Cereb Cortex. 2014;24:377-384. doi: 10.1093/cercor/bhs317
95. Catuara-Solarz S, Espinosa-Carrasco J, Erb I, et al. Principal Component Analysis of the Effects of Environmental Enrichment and (-)-epigallocatechin-3-gallate on Age-Associated Learning Deficits in a Mouse Model of Down Syndrome. eNeuro. 2016;3(5). pii: ENEURO.0103-16.2016Begenisic T, Sansevero G, Baroncelli L, et al. Early environmental therapy rescues brain development in a mouse model of Down syndrome. Neurobiol Dis. 2015;82:409-419. doi: 10.1016/j.nbd.2015.07.014.Bourne J, Harris KM. Do thin spines learn to be mushroom spines that remember? Curr Opin Neurobiol. 2007;17:381-386. doi: 10.1016/j.conb.2007.04.009
2. Arias-Trejo N, Barron-Martinez JB. Languaje skill in Down syndrome. In Auza Benavides A, Schwartz RG, ed. Language development and disorders in Spanish-speaking children. Springer; 2017: 329-341
3. Carlesimo GA, Marotta L, Vicari S. Long-term memory in mental retardation: evidence for a specific impairment in subjects with Down's syndrome Neuropsychol. 1997;35:71-79. doi: 10.1016/s0028-3932(96)00055-3
4. Chapman RS, Hesketh LJ. Behavioral phenotype of individuals with Down syndrome. Ment Retard Dev Disabil Res Rev. 2000;6:84-95. doi: 10.1002/1098-2779(2000)6:2<84::AID-MRDD2>3.0.CO;2-P
5. Angulo-Chavira AQ, García O, Arias-Trejo N. Pupil response and attention skills in Down syndrome. Res Dev Disabil. 2017;70:40-49. doi: 10.1016/j.ridd.2017.08.011
6. Vicari S. Motor development and neuropsychological patterns in persons with Down syndrome. Behav Genet. 2006;36:355-364. doi: 10.1007/s10519-006-9057-8
7. Dierssen M. Down syndrome: the brain in trisomic mode. Nat Rev Neurosci. 2012;13:844-858. doi: 10.1038/nrn3314
8. Ponroy Bally B, Murai KK. Astrocytes in Down Syndrome Across the Lifespan. Front Cell Neurosci. 2021;15:702685. doi: 10.3389/fncel.2021.702685.
9. Garcia O, Flores-Aguilar L. Astroglial and microglial pathology in Down syndrome: Focus on Alzheimer's disease. Front Cell Neurosci. 2022;16:987212. doi: 10.3389/fncel.2022.987212
10. Olmos-Serrano JL, Kang HJ, Tyler WA, et al. Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination. Neuron. 2016;89:1208-1222. doi: 10.1016/j.neuron.2016.01.042.
11. Nithianantharajah J, Hannan AJ. Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci. 2006;7:697-709. doi: 10.1038/nrn1970
12. Kempermann G. Environmental enrichment, new neurons and the neurobiology of individuality. Nat Rev Neurosci. 2019;20:235-245. doi: 10.1038/s41583-019-0120-x.
13. Hirase H, Shinohara Y. Transformation of cortical and hippocampal neural circuit by environmental enrichment. Neurosci. 2014;280:282-298. doi: 10.1016/j.neuroscience.2014.09.031
14. Moser MB, Trommald M, Egeland T, et al. Spatial training in a complex environment and isolation alter the spine distribution differently in rat CA1 pyramidal cells. J Comp Neurol. 1997;380(3):373-381. doi: 10.1002/(sici)1096-9861(19970414)380:3<373::aid-cne6>3.0.co;2-#
15. Sutherland R, Gibb R, Kolb B. The hippocampus makes a significant contribution to experience-dependent neocortical plasticity. Behav Brain Res. 2010;214:121-124. doi: 10.1016/j.bbr.2010.05.051.
16. Gelfo F, De Bartolo P, Giovine A, et al. Layer and regional effects of environmental enrichment on the pyramidal neuron morphology of the rat. Neurobiol Learn Mem. 2009;91:353-365.
17. Landers MS, Knott GW, Lipp HP, et al. Synapse formation in adult barrel cortex following naturalistic environmental enrichment. Neurosci. 2011;199:143-152. doi: 10.1016/j.neuroscience.2011.10.040.
18. Martin YB, Negredo P, Avendaño C. Experience-dependent plasticity in early stations of sensory processing in mature brains: effects of environmental enrichment on dendrite measures in trigeminal nuclei. Brain Struct Funct. 2022;227:865-879. doi: 10.1007/s00429-021-02424-3.
19. Hines S, Bennett F. Effectiveness of early interventions for children with Down syndrome. Ment Retard Dev Disabil Res Rev. 1996;2:96-101
20. Dierssen M, Benavides-Piccione R, Martínez-Cué C, et al. Alterations of neocortical pyramidal cell phenotype in the Ts65Dn mouse model of Down syndrome: effects of environmental enrichment. Cereb Cortex. 2003;13:758-764. doi:10.1093/cercor/13.7.758
21. De Giorgio A. The roles of motor activity and environmental enrichment in intellectual disability. Somatosens Mot Res. 2017;34:34-43. doi: 10.1080/08990220.2016.1278204
22. Kondo MA, Gray LJ, Pelka GJ, et al. Affective dysfunction in a mouse model of Rett syndrome: Therapeutic effects of environmental stimulation and physical activity. Dev Neurobiol. 2016;76:209-224. doi: 10.1002/dneu.22308
23. Downs J, Rodger J, Li C, et al. Environmental enrichment intervention for Rett syndrome: an individually randomised stepped wedge trial. Orphanet J Rare Dis. 2018;13:3. doi: 10.1186/s13023-017-0752-8.
24. Restivo L, Ferrari F, Passino E, et al. Enriched environment promotes behavioral and morphological recovery in a mouse model for the fragile X syndrome. Proc Natl Acad Sci USA. 2005;102:11557-11562. doi: 10.1073/pnas.0504984102
25. Winarni TI, Schneider A, Borodyanskara M, et al. Early intervention combined with targeted treatment promotes cognitive and behavioral improvements in young children with fragile X syndrome. Case Rep Genet. 2012;2012:280813. doi: 10.1155/2012/280813
26. Woo CC, Donnelly JH, Steinberg-Epstein R, et al. Environmental enrichment as a therapy for autism: A clinical trial replication and extension. Behav Neurosci. 2015;129:412-422. doi: 10.1037/bne0000068
27. Aronoff E, Hillyer R, Leon M. Environmental Enrichment Therapy for Autism: Outcomes with Increased Access. Neural Plast. 2016;2016:2734915. Epub. doi: 10.1155/2016/2734915
28. Yamaguchi H, Hara Y, Ago Y, et al. Environmental enrichment attenuates behavioral abnormalities in valproic acid-exposed autism model mice. Behav Brain Res. 2017;333:67-73. doi: 10.1016/j.bbr.2017.06.035.
29. Frese S, Petersen JA, Ligon-Auer M, et al. Exercise effects in Huntington disease. J Neurol. 2017;264:32-39. doi: 10.1007/s00415-016-8310-1.
30. Novati A, Nguyen HP, Schulze-Hentrich J. Environmental stimulation in Huntington disease patients and animal models. Neurobiol Dis. 2022;171:105725. doi: 10.1016/j.nbd.2022.105725.
31. Stazi M, Wirths O. Physical activity and cognitive stimulation ameliorate learning and motor deficits in a transgenic mouse model of Alzheimer's disease. Behav Brain Res. 2021;15:397:112951. doi: 10.1016/j.bbr.2020.112951
32. Lazarov O, Robinson J, Tang YP, et al. Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. Cell. 2005;120:701-713. doi: 10.1016/j.cell.2005.01.015
33. Pedrinolla A, Venturelli M, Fonte C, et al. Exercise Training on Locomotion in Patients with Alzheimer's Disease: A Feasibility Study. J Alzheimers Dis. 2018;61:1599-1609. doi: 10.3233/JAD-170625
34. Campelo CLC, Santos JR, Silva AF, et al. Exposure to an enriched environment facilitates motor recovery and prevents short-term memory impairment and reduction of striatal BDNF in a progressive pharmacological model of parkinsonism in mice. Behav Brain Res. 2017;328:138-148. doi: 10.1016/j.bbr.2017.04.028
35. Jadavji NM, Kolb B, Metz GA. Enriched environment improves motor function in intact and unilateral dopamine-depleted rats. Neurosci. 2006;140: 1127-1138. doi: 10.1016/j.neuroscience.2006.03.027
36. O'Shea KS, Liu LH, Dixit VM. Thrombospondin and a 140 kd fragment promote adhesion and neurite outgrowth from embryonic central and peripheral neurons and from PC12 cells. Neuron. 1991; 91:231-237. Doi: 10.1016/0896-6273(91)90261-w
37. Osterhout DJ, Frazier WA, Higgins D. Thrombospondin promotes process outgrowth in neurons from the peripheral and central nervous systems. Dev Biol. 1992;150:256-265. doi: 10.1016/0012-1606(92)90240-h
38. Yu K, Ge J, Summers JB, et al. TSP-1 secreted by bone marrow stromal cells contributes to retinal ganglion cell neurite outgrowth and survival. PLoS One. 2008;3:e2470. doi: 10.1371/journal.pone.0002470.
39. Pu Y, Meng K, Gu C, et al. Thrombospondin-1 modified bone marrow mesenchymal stem cells (BMSCs) promote neurite outgrowth and functional recovery in rats with spinal cord injury. Oncotarget. 2017;8:96276-96289. doi: 10.18632/oncotarget.22018.
40. DeFreitas MF, Yoshida CK, Frazier WA, et al. Identification of integrin alpha 3 beta 1 as a neuronal thrombospondin receptor mediating neurite outgrowth. Neuron. 1995;15:333-343. doi: 10.1016/0896-6273(95)90038-1
41. Lu Z, Kipnis J. Thrombospondin 1-a key astrocyte-derived neurogenic factor. FASEB J. 2010;24:1925-1934. doi: 10.1096/fj.09-150573
42. Christopherson KS, Ullian EM, Stokes CC, et al. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell. 2005;120:421-433. Doi : 10.1016/j.cell.2004.12.020
43. Eroglu C, Allen NJ, Susman MW, et al. Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell. 2009;139:380-392. doi: 10.1016/j.cell.2009.09.025
44. Xu J, Xiao N, Xia J. Thrombospondin 1 accelerates synaptogenesis in hippocampal neurons through neuroligin 1. Nat Neurosci. 2010;13:22-24. doi: 10.1038/nn.2459
45. Mendus D, Sundaresan S, Grillet N, et al. Thrombospondins 1 and 2 are important for afferent synapse formation and function in the inner ear. Eur J Neurosci. 2014;39:1256-1267. doi: 10.1111/ejn.12486
46. Garcia O, Torres M, Helguera P, et al. A role for thrombospondin-1 deficits in astrocyte-mediated spine and synaptic pathology in Down's syndrome. PLoS One. 2010;5:e14200. doi: 10.1371/journal.pone.0014200.
47. Cheng C, Lau SK, Doering LC. Astrocyte-secreted thrombospondin-1 modulates synapse and spine defects in the fragile X mouse model. Mol Brain. 2016;9:74. doi: 10.1186/s13041-016-0256-9
48. Torres MD, Garcia O, Tang C, et al. Dendritic spine pathology and thrombospondin-1 deficits in Down syndrome. Free Radic Biol Med. 2018;114:10-14. doi: 10.1016/j.freeradbiomed.2017.09.025
49. Bray ER, Yungher BJ, Levay K, et al. Thrombospondin-1 Mediates Axon Regeneration in Retinal Ganglion Cells. Neuron. 2019;103:642-657 doi: 10.1016/j.neuron.2019.05.044
50. Liauw J, Hoang S, Choi M, et al. Thrombospondins 1 and 2 are necessary for synaptic plasticity and functional recovery after stroke. J Cereb Blood Flow Metab. 2008;28:1722-1732. doi: 10.1038/jcbfm.2008.65
51. Mendus D, Rankin-Gee EK, Mustapha M, et al. Increased sensitivity to kindling in mice lacking TSP1 Neurosci. 2015;305:302-308. doi: 10.1016/j.neuroscience.2015.07.075.
52. Nagai J, Rajbhandari AK, Gangwani MR, et al. Hyperactivity with Disrupted Attention by Activation of an Astrocyte Synaptogenic Cue. Cell. 2019; 177(5):1280-1292. doi: 10.1016/j.cell.2019.03.019.
53. Sztainberg Y, Chen A. An environmental enrichment model for mice. Nat Protoc. 2010;5:1535-1539. doi: 10.1038/nprot.2010.114.
54. Helguera P, Pelsman A, Pigino G, et al. ets-2 promotes the activation of a mitochondrial death pathway in Down's syndrome neurons. J Neurosci. 2005;25:2295-2303. doi: 10.1523/JNEUROSCI.5107-04.2005
55. Barón-Mendoza I, Del Moral-Sánchez I, Martínez-Marcial M, et al. Dendritic complexity in prefrontal cortex and hippocampus of the autistic-like mice C58/J. Neurosci Lett. 2019;703:149-155. doi: 10.1016/j.neulet.2019.03.018
56. Langhammer CG, Previtera ML, Sweet ES, et al. Automated Sholl analysis of digitized neuronal morphology at multiple scales: Whole cell Sholl analysis versus Sholl analysis of arbor subregions. Cytometry A. 2010;77:1160-1168. doi: 10.1002/cyto.a.20954.
57. Orlowski D, Bjarkam CR. A simple reproducible and time saving method of semi-automatic dendrite spine density estimation compared to manual spine counting. J Neurosci Meth. 2012;208:128-133. doi: 10.1016/j.jneumeth.2012.05.009
58. Risher WC, Ustunkaya T, Singh Alvarado J, et al. Rapid Golgi analysis method for efficient and unbiased classification of dendritic spines. PLoS One. 2014;10;9(9):e107591. doi: 10.1371/journal.pone.0107591
59. Sultan F. Dissection of different areas from mouse hippocampus. Bio Protoc. 2013;3(21). pii: e955
60. Binley KE, Ng WS, Tribble JR, et al. Sholl analysis: a quantitative comparison of semi-automated methods. J Neurosci Meth. 2014;225: 65-70. doi: 10.1016/j.jneumeth.2014.01.017
61. Zhao C, Isenberg JS, Popel AS. Human expression patterns: qualitative and quantitative analysis of thrombospondin-1 under physiological and pathological conditions. J Cell Mol Med. 2018;22:2086-2097. doi: 10.1111/jcmm.13565
62. Asch AS, Leung LL, Shapiro J, et al. Human brain glial cells synthesize thrombospondin. Proc Natl Acad Sci USA. 1986; 83:2904-2908. doi: 10.1073/pnas.83.9.2904
63. Iruela-Arispe ML, Liska DJ, Sage EH, et al. Differential expression of thrombospondin 1, 2, and 3 during murine development. Dev Dyn. 1993;197:40-56. doi: 10.1002/aja.1001970105
64. Buée L, Hof PR, Roberts DD, et al. Immunohistochemical identification of thrombospondin in normal human brain and in Alzheimer's disease. Am J Pathol. 1992;141:783-788.
65. Dierssen M, Ramakers GJ. Dendritic pathology in mental retardation: from molecular genetic to neurobiology. Genes Brain Behav. 2006;5 Suppl 2:48-60. Doi: 10.1111/j.1601-183X.2006.00224.x
66. Nishiwaki T, Yamaguchi T, Zhao C, et al. Reduced expression of thrombospondins and craniofacial dysmorphism in mice overexpressing Fra1. J Bone Miner Res. 2006; 21: 596–604 doi: 10.1359/jbmr.051216
67. Antonarakis SE, Skotko BG, Rafii MS, et al. Down syndrome. Nat Rev Dis Primers. 2020; 6;6(1):9. doi: 10.1038/s41572-019-0143-7.
68. Faherty CJ, Kerley D, Smeyne RJ. A Golgi-Cox morphological analysis of neuronal changes induced by environmental enrichment. Brain Res Dev Brain Res. 2003;141:55-61. doi: 10.1016/s0165-3806(02)00642-9
69. Kolb B, Gorny G, Soderpalm AH, et al. Environmental complexity has different effects on the structure of neurons in the prefrontal cortex versus the parietal cortex or nucleus accumbens. Synapse. 2003;48(3): 149-153. doi: 10.1002/syn.10196
70. Bose M, Munoz-Llancao P, Roychowdhury S, et al. Effect of the environment on the dendritic morphology of the rat auditory cortex. Synapse. 2010;64:97-110. doi: 10.1002/syn.20710
71. Rampon C, Jiang CH, Dong H, et al. Effects of environmental enrichment on gene expression in the brain. Proc Natl Acad Sci USA. 2000;97:12880-12884. doi: 10.1073/pnas.97.23.12880
72. Malik R, Chattarji S. Enhanced intrinsic excitability and EPSP-spike coupling accompany enriched environment-induced facilitation of LTP in hippocampal CA1 pyramidal neurons. J Neurophysiol. 2012;107:1366-1378. doi: 10.1152/jn.01009.2011
73. Bindu B, Alladi PA, Mansooralikhan BM, et al. Short-term exposure to an enriched environment enhances dendritic branching but not brain-derived neurotrophic factor expression in the hippocampus of rats with ventral subicular lesions. Neurosci. 2007;144:412-423. doi: 10.1016/j.neuroscience.2006.09.057
74. Lushnikova I, Skibo G, Muller D, et al. Synaptic potentiation induces increased glial coverage of excitatory synapses in CA1 hippocampus. Hippocampus. 2009;19:753-762. doi: 10.1002/hipo.20551
75. Zhao M, Choi YS, Obrietan K, et al. Synaptic plasticity (and the lack thereof) in hippocampal CA2 neurons. J Neurosci. 2007;27:12025-12032. doi: 10.1523/JNEUROSCI.4094-07.2007
76. Simons SB, Escobedo Y, Yasuda R, et al. Regional differences in hippocampal calcium handling provide a cellular mechanism for limiting plasticity. Proc Natl Acad Sci USA. 2009;106:14080-14084. doi: 10.1073/pnas.0904775106.
77. Kohara K, Pignatelli M, Rivest AJ, et al. Cell type-specific genetic and optogenetic tools reveal hippocampal CA2 circuits. Nat Neurosci. 2014;17: 269-279. doi: 10.1073/pnas.0904775106
78. Dudek SM, Alexander GM, Farris S. Rediscovering area CA2: unique properties and functions. Nat Rev Neurosci. 2016;17:89-102. doi: 10.1038/nrn.2015.22
79. Hitti FL, Siegelbaum SA. The hippocampal CA2 region is essential for social memory. Nature. 2014;508(7494): 88-92. Doi: 10.1038/nrn.2015.22
80. Stevenson EL, Caldwell HK. Lesions to the CA2 region of the hippocampus impair social memory in mice. Eur J Neurosci. 2014;40(9): 3294-3301. doi: 10.1111/ejn.12689
81. Pennington BF, Moon J, Edgin J, et al. The neuropsychology of Down syndrome: evidence for hippocampal dysfunction. Child Dev. 2003;74:75-93. Doi: 10.1111/1467-8624.00522
82. Powers BE, Santiago NA, Strupp BJ. Rapid forgetting of social learning in the Ts65Dn mouse model of Down syndrome: New evidence for hippocampal dysfunction. Behav Neurosci. 2018;132:51-56. doi: 10.1037/bne0000227
83. Redila VA, Christie BR. Exercise-induced changes in dendritic structure and complexity in the adult hippocampal dentate gyrus. Neurosci. 2006;137:1299-1307. doi: 10.1016/j.neuroscience.2005.10.050
84. Tashiro A, Makino H, Gage FH. Experience-specific functional modification of the dentate gyrus through adult neurogenesis: a critical period during an immature stage. J Neurosci. 2007;27:3252-3259. Doi: 10.1523/JNEUROSCI.4941-06.2007
85. Pereira AC, Huddleston DE, Brickman AM, et al. An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci USA. 2007;104:5638-5643. doi: 10.1073/pnas.0611721104
86. Eadie BD, Redila VA, Christie BR. Voluntary exercise alters the cytoarchitecture of the adult dentate gyrus by increasing cellular proliferation, dendritic complexity, and spine density. J Comp Neurol. 2005;486:39-47. doi: 10.1002/cne.20493
87. Gallitano AL, Satvat E, Gil M, et al. Distinct dendritic morphology across the blades of the rodent dentate gyrus. Synapse. 2016;70:277-282. doi: 10.1002/syn.21900.
88. Chakrabarti L, Scafidi J, Gallo V, et al. Environmental enrichment rescues postnatal neurogenesis defect in the male and female Ts65Dn mouse model of Down syndrome. Dev Neurosci. 2011;33:428-441. doi: 10.1159/000329423.
89. Perry VH, Maffei L. Dendritic competition: competition for what? Brain Res. 1988;469:195-208. doi: 10.1016/0165-3806(88)90182-4
90. McAllister, AK. Cellular and molecular mechanisms of dendrite growth. Cereb Cortex. 2000;10: 963-973. doi: 10.1093/cercor/10.10.963
91. Takashima S, Becker LE, Armstrong DL, et al. Abnormal neuronal development in the visual cortex of the human fetus and infant with down's syndrome. A quantitative and qualitative Golgi study. Brain Res. 1981;225:1-21. doi: 10.1016/0006-8993(81)90314-0
92. Villarroya O, Ballestín R, López-Hidalgo R, et al. Morphological alterations in the hippocampus of the Ts65Dn mouse model for Down Syndrome correlate with structural plasticity markers. Histol Histopathol. 2018;33:101-115. doi: 10.14670/HH-11-894
93. Becker LE, Armstrong DL, Chan F. Dendritic atrophy in children with Down's syndrome. Ann Neurol. 1986;20:520-526. doi: 10.1002/ana.410200413
94. Jung CK, Herms J. Structural dynamics of dendritic spines are influenced by an environmental enrichment: an in vivo imaging study. Cereb Cortex. 2014;24:377-384. doi: 10.1093/cercor/bhs317
95. Catuara-Solarz S, Espinosa-Carrasco J, Erb I, et al. Principal Component Analysis of the Effects of Environmental Enrichment and (-)-epigallocatechin-3-gallate on Age-Associated Learning Deficits in a Mouse Model of Down Syndrome. eNeuro. 2016;3(5). pii: ENEURO.0103-16.2016Begenisic T, Sansevero G, Baroncelli L, et al. Early environmental therapy rescues brain development in a mouse model of Down syndrome. Neurobiol Dis. 2015;82:409-419. doi: 10.1016/j.nbd.2015.07.014.Bourne J, Harris KM. Do thin spines learn to be mushroom spines that remember? Curr Opin Neurobiol. 2007;17:381-386. doi: 10.1016/j.conb.2007.04.009