CoChat
Sign Up
Cited by 37Down syndrome and intellectual disability researchMemory and Neural MechanismsAlzheimer's disease research and treatments

Signalling pathways contributing to learning and memory deficits in the Ts65Dn mouse model of Down syndrome

Open access
Freeburn, Aimée, Munn, Robert Gordon Keith·2021·Neuronal Signaling
DOI 10.1042/ns20200011PMC PMC7955101
Open this paper in CoChat — free account

Abstract

Down syndrome (DS) is a genetic trisomic disorder that produces life-long changes in physiology and cognition. Many of the changes in learning and memory seen in DS are reminiscent of disorders involving the hippocampal/entorhinal circuit. Mouse models of DS typically involve trisomy of murine chromosome 16 is homologous for many of the genes triplicated in human trisomy 21, and provide us with good models of changes in, and potential pharmacotherapy for, human DS. Recent careful dissection of the Ts65Dn mouse model of DS has revealed differences in key signalling pathways from the basal forebrain to the hippocampus and associated rhinal cortices, as well as changes in the microstructure of the hippocampus itself. In vivo behavioural and electrophysiological studies have shown that Ts65Dn animals have difficulties in spatial memory that mirror hippocampal deficits, and have changes in hippocampal electrophysiological phenomenology that may explain these differences, and align with expectations generated from in vitro exploration of this model. Finally, given the existing data, we will examine the possibility for pharmacotherapy for DS, and outline the work that remains to be done to fully understand this system.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1042/ns20200011

Cites

7 of 7 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Mouse models have allowed advances in deciphering mechanisms governing brain development and function and the consequences of Down syndrome-related manipulations.

    “These models have allowed the scientific community to make incredible advances in deciphering the mechanisms governing brain development and function, as well as the consequences of DS-related manipulations for those mechanisms18–22.”

    From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [18]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 162

  1. [1]Weijerman M.E. and de Winter J.P. (2010) Clinical practice: the care of children with Down syndrome. Eur. J. Pediatr. 169, 1445– 1452 10.1007/s00431-010-1253-0 20632187 PMC2962780 · DOI
  2. [2]Reilly C. (2012) Behavioural phenotypes and special educational needs: is aetiology important in the classroom? J. Intell. Disabil. Res. 56, 929– 946 10.1111/j.1365-2788.2012.01542.x 22471356 · DOI
  3. [3]Jarrold C., Baddeley A.D. and Phillips C. (2007) Long-term memory for verbal and visual information in down syndrome and williams syndrome: performance on the Doors and People Test. Cortex 43, 233– 247 10.1016/S0010-9452(08)70478-7 17405669 · DOI
  4. [4]Crissman B.G., Worley G., Roizen N. and Kishnani P.S. (2006) Current perspectives on Down syndrome: Selected medical and social issues. Am. J. Med. Genet. 142C, 127– 130 10.1002/ajmg.c.30099 17048353 · DOI
  5. [5]Roizen N.J. and Patterson D. (2003) Down’s syndrome. Lancet 361, 1281– 1289 10.1016/S0140-6736(03)12987-X 12699967 · DOI
  6. [6]Martínez M.H., Duran X.P. and Navarro J.N. (2011) Attention deficit disorder with or without hyperactivity or impulsivity in children with Down's syndrome. Int. Med. Rev. Down Syndr. 15, 18– 22 10.1016/S2171-9748(11)70006-X · DOI
  7. [7]Ekstein S., Glick B., Weill M., Kay B. and Berger I. (2011) Down Syndrome and Attention-Deficit/Hyperactivity Disorder (ADHD). J. Child Neurol. 26, 1290– 1295 10.1177/0883073811405201 21628698 · DOI
  8. [8]Peñuelas B.G. (2010) Depression and Down syndrome. Int. Medical Rev. Down Syndr. 14, 14– 16 10.1016/S2171-9748(10)70004-0 · DOI
  9. [9]Collacott R.A., Cooper S.-A. and McGrother C. (1992) Differential rates of psychiatric disorders in adults with Down’s syndrome compared with other mentally handicapped adults. Br. J. Psychiatry 161, 671– 674 10.1192/bjp.161.5.671 1422617 · DOI
  10. [10]Myers B.A. and Pueschel S.M. (1991) Psychiatric disorders in persons with Down Syndrome. J. Nerv. Ment. Dis. 179, 609– 613 10.1097/00005053-199110000-00004 1833506 · DOI
  11. [11]Prasher V.P. and Day S. (1995) Brief report: Obsessive-compulsive disorder in adults with Down’s Syndrome. J. Autism Dev. Disord. 25, 453– 458 10.1007/BF02179379 7592255 · DOI
  12. [12]Pennington B.F., Moon J., Edgin J., Stedron J. and Nadel L. (2003) The neuropsychology of Down Syndrome: evidence for hippocampal dysfunction. Child Dev. 74, 75– 93 10.1111/1467-8624.00522 12625437 · DOI · Paper page
  13. [13]Spanò G. and Edgin J.O. (2016) Everyday memory in individuals with Down syndrome: validation of the Observer Memory Questionnaire – Parent Form. Child Neuropsychol. 23, 1– 13 26981787
  14. [14]Lanfranchi S., Mammarella I.C. and Carretti B. (2014) Spatial-simultaneous working memory and selective interference in Down syndrome. Child Neuropsychol. 21, 481– 489 10.1080/09297049.2014.913557 24814650 · DOI
  15. [15]Carretti B. and Lanfranchi S. (2010) The effect of configuration on VSWM performance of Down syndrome individuals. J. Intell. Disabil. Res. 54, 1058– 1066 10.1111/j.1365-2788.2010.01334.x 21029233 · DOI
  16. [16]Lavenex P.B. et al. (2015) Allocentric spatial learning and memory deficits in Down syndrome. Front. Psychol. 6, 62 10.3389/fpsyg.2015.00062 25762946 PMC4329802 · DOI
  17. [17]O'Keefe J. and Dostrovsky J. (1971) The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat. Brain Res. 34, 171– 175 10.1016/0006-8993(71)90358-1 5124915 · DOI · Paper page
  18. [18]Hafting T., Fyhn M., Molden S., Moser M.-B. and Moser E.I. (2005) Microstructure of a spatial map in the entorhinal cortex. Nature 436, 801– 806 10.1038/nature03721 15965463 · DOI · Paper page
  19. [19]Sargolini F. et al. (2006) Conjunctive representation of position, direction, and velocity in entorhinal cortex. Science 312, 758– 762 10.1126/science.1125572 16675704 · DOI · Paper page
  20. [20]Hinman J.R., Brandon M.P., Climer J.R., Chapman W.G. and Hasselmo M.E. (2016) Multiple running speed signals in medial entorhinal cortex. Neuron 91, 666– 679 10.1016/j.neuron.2016.06.027 27427460 PMC4976037 · DOI
  21. [21]Kropff E., Carmichael J.E., Moser M.-B. and Moser E.I. (2015) Speed cells in the medial entorhinal cortex. Nature 523, 419– 424 10.1038/nature14622 26176924 · DOI · Paper page
  22. [22]Hales J.B. et al. (2014) Medial entorhinal cortex lesions only partially disrupt hippocampal place cells and hippocampus-dependent place memory. Cell Rep. 9, 893– 901 10.1016/j.celrep.2014.10.009 25437546 PMC4294707 · DOI · Paper page
  23. [23]Bonnevie T. et al. (2013) Grid cells require excitatory drive from the hippocampus. Nat. Neurosci. 16, 309– 317 10.1038/nn.3311 23334581 · DOI
  24. [24]Winson J. (1978) Loss of hippocampal theta rhythm results in spatial memory deficit in the rat. Science 201, 160– 163 10.1126/science.663646 663646 · DOI
  25. [25]Givens B.S. and Olton D.S. (1990) Cholinergic and GABAergic modulation of medial septal area: Effect on working memory. Behav. Neurosci. 104, 849– 855 10.1037/0735-7044.104.6.849 2178347 · DOI
  26. [26]Aggleton J.P., Neave N., Nagle S. and Hunt P.R. (1995) A comparison of the effects of anterior thalamic, mamillary body and fornix lesions on reinforced spatial alternation. Behav. Brain Res. 68, 91– 101 10.1016/0166-4328(94)00163-A 7619309 · DOI
  27. [27]M'Harzi M. et al. (1987) Effects of selective lesions of Fimbria-Fornix on learning set in the rat. Physiol. Behav. 40, 181– 188 10.1016/0031-9384(87)90205-8 3628526 · DOI
  28. [28]Numan R. and Quaranta J.R. (1990) Effects of medial septal lesions on operant delayed alternation in rats. Brain Res. 531, 232– 241 10.1016/0006-8993(90)90779-B 2289124 · DOI
  29. [29]Kloc M.L., Velasquez F., Niedecker R.W., Barry J.M. and Holmes G.L. (2020) Disruption of hippocampal rhythms via optogenetic stimulation during the critical period for memory development impairs spatial cognition. Brain Stimuli 13, 1535– 1547 10.1016/j.brs.2020.08.011 32871261 PMC7953993 · DOI
  30. [30]Tsodyks M.V., Skaggs W.E., Sejnowski T.J. and McNaughton B.L. (1996) Population dynamics and theta rhythm phase precession of hippocampal place cell firing: a spiking neuron model. Hippocampus 6, 271– 280 10.1002/(SICI)1098-1063(1996)6:3<271::AID-HIPO5>3.0.CO;2-Q 8841826 · DOI
  31. [31]Skaggs W.E., McNaughton B.L., Wilson M.A. and Barnes C.A. (1996) Theta phase precession in hippocampal neuronal populations and the compression of temporal sequences. Hippocampus 6, 149– 172 10.1002/(SICI)1098-1063(1996)6:2<149::AID-HIPO6>3.0.CO;2-K 8797016 · DOI
  32. [32]Manns J.R., Zilli E.A., Ong K.C., Hasselmo M.E. and Eichenbaum H. (2007) Hippocampal CA1 spiking during encoding and retrieval: Relation to theta phase. Neurobiol. Learn. Mem. 87, 9– 20 10.1016/j.nlm.2006.05.007 16839788 · DOI
  33. [33]Hasselmo M.E., Bodelón C. and Wyble B.P. (2002) A proposed function for hippocampal theta rhythm: separate phases of encoding and retrieval enhance reversal of prior learning. Neural Comput. 14, 793– 817 10.1162/089976602317318965 11936962 · DOI · Paper page
  34. [34]Mitchell S.J. and Ranck J.B. (1980) Generation of theta rhythm in medial entorhinal cortex of freely moving rats. Brain Res. 189, 49– 66 10.1016/0006-8993(80)90006-2 7363097 · DOI
  35. [35]Deshmukh S.S., Yoganarasimha D., Voicu H. and Knierim J.J. (2010) Theta modulation in the medial and the lateral entorhinal cortices. J. Neurophysiol. 104, 994– 1006 10.1152/jn.01141.2009 20505130 PMC2934945 · DOI
  36. [36]Mitchell S., Rawlins J., Steward O. and Olton D. (1982) Medial septal area lesions disrupt theta rhythm and cholinergic staining in medial entorhinal cortex and produce impaired radial arm maze behavior in rats. J. Neurosci. 2, 292– 302 10.1523/JNEUROSCI.02-03-00292.1982 7062110 PMC6564337 · DOI
  37. [37]Reifenstein E.T., Kempter R., Schreiber S., Stemmler M.B. and Herz A.V. (2012) Grid cells in rat entorhinal cortex encode physical space with independent firing fields and phase precession at the single-trial level. Proc. Natl. Acad. Sci. U.S.A. 109, 6301– 6306 10.1073/pnas.1109599109 22474395 PMC3341055 · DOI
  38. [38]Hafting T., Fyhn M., Bonnevie T., Moser M.-B. and Moser E.I. (2008) Hippocampus-independent phase precession in entorhinal grid cells. Nature 453, 1248– 1252 10.1038/nature06957 18480753 · DOI
  39. [39]Climer J.R., Newman E.L. and Hasselmo M.E. (2013) Phase coding by grid cells in unconstrained environments: two‐dimensional phase precession. Eur. J. Neurosci. 38, 2526– 2541 10.1111/ejn.12256 23718553 PMC3912569 · DOI
  40. [40]Navratilova Z., Giocomo L.M., Fellous J., Hasselmo M.E. and McNaughton B.L. (2012) Phase precession and variable spatial scaling in a periodic attractor map model of medial entorhinal grid cells with realistic after‐spike dynamics. Hippocampus 22, 772– 789 10.1002/hipo.20939 21484936 · DOI
  41. [41]Ebbesen C.L. et al. (2016) Cell type-specific differences in spike timing and spike shape in the rat parasubiculum and superficial medial entorhinal cortex. Cell Rep. 16, 1005– 1015 10.1016/j.celrep.2016.06.057 27425616 PMC4967475 · DOI
  42. [42]Brandon M.P., Bogaard A.R., Schultheiss N.W. and Hasselmo M.E. (2013) Segregation of cortical head direction cell assemblies on alternating theta cycles. Nat. Neurosci. 16, 739– 748 10.1038/nn.3383 23603709 PMC3703458 · DOI
  43. [43]Lee M.G., Chrobak J.J., Sik A., Wiley R.G. and Buzsáki G. (1994) Hippocampal theta activity following selective lesion of the septal cholinergic systeM. Neuroscience 62, 1033– 1047 10.1016/0306-4522(94)90341-7 7845584 · DOI
  44. [44]Donovick P.J. (1968) Effects of localized septal lesions on hippocampal EEG activity and behavior in rats. J. Comp. Physiol. Psych. 66, 569– 578 10.1037/h0026514 5721486 · DOI
  45. [45]Buzsáki G., Leung L.-W.S. and Vanderwolf C.H. (1983) Cellular bases of hippocampal EEG in the behaving rat. Brain Res. Rev. 6, 139– 171 10.1016/0165-0173(83)90037-1 6357356 · DOI
  46. [46]Sainsbury R.S. and Bland B.H. (1981) The effects of selective septal lesions on theta production in CA1 and the dentate gyrus of the hippocampus. Physiol. Behav. 26, 1097– 1101 10.1016/0031-9384(81)90214-6 7280071 · DOI
  47. [47]Leutgeb S. and Mizumori S.J. (1999) Excitotoxic septal lesions result in spatial memory deficits and altered flexibility of hippocampal single-unit representations. J. Neurosci. 19, 6661– 6672 10.1523/JNEUROSCI.19-15-06661.1999 10414995 PMC6782835 · DOI
  48. [48]Meck W., Church R., Wenk G. and Olton D. (1987) Nucleus basalis magnocellularis and medial septal area lesions differentially impair temporal memory. J. Neurosci. 7, 3505– 3511 10.1523/JNEUROSCI.07-11-03505.1987 3681402 PMC6569024 · DOI
  49. [49]Myers C.E. and Scharfman H.E. (2011) Pattern separation in the dentate gyrus: a role for the CA3 backprojection. Hippocampus 21, 1190– 1215 10.1002/hipo.20828 20683841 PMC2976779 · DOI
  50. [50]Kobayashi K. and Poo M. (2004) Spike train timing-dependent associative modification of hippocampal CA3 recurrent synapses by mossy fibers. Neuron 41, 445– 454 10.1016/S0896-6273(03)00873-0 14766182 · DOI
  51. [51]Rolls E.T. (2013) A quantitative theory of the functions of the hippocampal CA3 network in memory. Front. Cell Neurosci. 7, 98 10.3389/fncel.2013.00098 23805074 PMC3691555 · DOI
  52. [52]Rolls E.T. (2007) An attractor network in the hippocampus: theory and neurophysiology. Learn. Mem. 14, 714– 731 10.1101/lm.631207 18007016 · DOI
  53. [53]Lewis P.R. and Shute C.C.D. (1967) The cholinergic limbic system: projections to hippocampal formation, medial cortex, nuclei of the ascending cholinergic reticular system, and the subfornical organ and supra-optic crest. Brain 90, 521– 540 10.1093/brain/90.3.521 6058141 · DOI
  54. [54]Sotty F. et al. (2003) Distinct electrophysiological properties of glutamatergic, cholinergic and GABAergic rat septohippocampal neurons: novel implications for hippocampal rhythmicity. J. Physiol. 551, 927– 943 10.1113/jphysiol.2003.046847 12865506 PMC2343277 · DOI
  55. [55]Colom L.V., Castaneda M.T., Reyna T., Hernandez S. and Garrido‐sanabria E. (2005) Characterization of medial septal glutamatergic neurons and their projection to the hippocampus. Synapse 58, 151– 164 10.1002/syn.20184 16108008 · DOI
  56. [56]Köhler C., Chan-Palay V. and Wu J.-Y. (1984) Septal neurons containing glutamic acid decarboxylase immunoreactivity project to the hippocampal region in the rat brain. Anat. Embryol. 169, 41– 44 10.1007/BF00300585 6721220 · DOI
  57. [57]Unal G., Joshi A., Viney T.J., Kis V. and Somogyi P. (2015) Synaptic targets of medial septal projections in the hippocampus and extrahippocampal cortices of the mouse. J. Neurosci. 35, 15812– 15826 10.1523/JNEUROSCI.2639-15.2015 26631464 PMC4666911 · DOI
  58. [58]Cobb S., Buhl E., Halasy K., Paulsen O. and Somogyi P. (1995) Synchronization of neuronal activity in hippocampus by individual GABAergic interneurons. Nature 378, 75– 78 10.1038/378075a0 7477292 · DOI · Paper page
  59. [59]Pang K.C.H., Jiao X., Sinha S., Beck K.D. and Servatius R.J. (2011) Damage of GABAergic neurons in the medial septum impairs spatial working memory and extinction of active avoidance: effects on proactive interference. Hippocampus 21, 835– 846 20865731 PMC3010529
  60. [60]Smith H.R. and Pang K.C.H. (2005) Orexin-saporin lesions of the medial septum impair spatial memory. Neuroscience 132, 261– 271 10.1016/j.neuroscience.2004.12.037 15802181 · DOI
  61. [61]Yoder R.M. and Pang K.C.H. (2005) Involvement of GABAergic and cholinergic medial septal neurons in hippocampal theta rhythm. Hippocampus 15, 381– 392 10.1002/hipo.20062 15630696 · DOI
  62. [62]Oddie S.D., Kirk I.J., Whishaw I.Q. and Bland B.H. (1997) Hippocampal formation is involved in movement selection: evidence from medial septal cholinergic modulation and concurrent slow-wave (theta rhythm) recording. Behav. Brain Res. 88, 169– 180 10.1016/S0166-4328(97)02290-0 9404626 · DOI
  63. [63]Pan W.-X. and McNaughton N. (1997) The medial supramammillary nucleus, spatial learning and the frequency of hippocampal theta activity. Brain Res. 764, 101– 108 10.1016/S0006-8993(97)00431-9 9295198 · DOI
  64. [64]McNaughton N. et al. (1995) Contribution of synapses in the medial supramammillary nucleus to the frequency of hippocampal theta rhythm in freely moving rats. Hippocampus 5, 534– 545 10.1002/hipo.450050605 8646280 · DOI
  65. [65]McNaughton N., Richardson J. and Gore C. (1986) Reticular elicitation of hippocampal slow waves: Common effects of some anxiolytic drugs. Neuroscience 19, 899– 903 10.1016/0306-4522(86)90306-4 2879256 · DOI
  66. [66]McNaughton N., Kocsis B. and Hajós M. (2007) Elicited hippocampal theta rhythm: a screen for anxiolytic and procognitive drugs through changes in hippocampal function? Behav. Pharmacol. 18, 329– 346 10.1097/FBP.0b013e3282ee82e3 17762505 · DOI · Paper page
  67. [67]Liu Z., Peng C., Zhuang Y., Chen Y. and Behnisch T. (2020) Direct medial entorhinal cortex input to hippocampal CA3 is crucial for eEF2K inhibitor-induced neuronal oscillations in the mouse hippocampus. Front. Cell Neurosci. 14, 24 10.3389/fncel.2020.00024 32210764 PMC7069380 · DOI
  68. [68]Witter M.P., Canto C.B., Couey J.J., Koganezawa N. and O'Reilly K.C. (2014) Architecture of spatial circuits in the hippocampal region. Philos. Trans. R. Soc. B Biol. Sci. 369, 20120515 10.1098/rstb.2012.0515 PMC3866439 24366129 · DOI
  69. [69]Li Y. et al. (2017) A distinct entorhinal cortex to hippocampal CA1 direct circuit for olfactory associative learning. Nat. Neurosci. 20, 559– 570 10.1038/nn.4517 28263300 · DOI
  70. [70]Ohara S. et al. (2018) Intrinsic projections of layer Vb neurons to layers Va, III, and II in the lateral and medial entorhinal cortex of the rat. Cell Rep. 24, 107– 116 10.1016/j.celrep.2018.06.014 29972772 · DOI
  71. [71]Belichenko P.V., Kleschevnikov A.M., Salehi A., Epstein C.J. and Mobley W.C. (2007) Synaptic and cognitive abnormalities in mouse models of down syndrome: Exploring genotype‐phenotype relationships. J. Comp. Neurol. 504, 329– 345 10.1002/cne.21433 17663443 · DOI
  72. [72]Busciglio J., Capone G., O’Bryan J., O’Byran J.P. and Gardiner K.J. (2013) Down syndrome: genes, model systems, and progress towards pharmacotherapies and clinical trials for cognitive deficits. Cytogenet. Genome Res. 141, 260– 271 10.1159/000354306 24008277 · DOI
  73. [73]Herault Y. et al. (2017) Rodent models in Down syndrome research: impact and future opportunities. Dis. Model Mech. 10, 1165– 1186 10.1242/dmm.029728 28993310 PMC5665454 · DOI
  74. [74]Choi J.H.K. et al. (2009) Age‐dependent dysregulation of brain amyloid precursor protein in the Ts65Dn Down syndrome mouse model. J. Neurochem. 110, 1818– 1827 10.1111/j.1471-4159.2009.06277.x 19619138 PMC2744432 · DOI · Paper page
  75. [75]Hyde L.A. and Crnic L.S. (2001) Age-related deficits in context discrimination learning in Ts65Dn mice that model Down syndrome and Alzheimer’s disease. Behav. Neurosci. 115, 1239– 1246 10.1037/0735-7044.115.6.1239 11770055 · DOI
  76. [76]Olmos-Serrano J.L., Tyler W.A., Cabral H.J. and Haydar T.F. (2016) Longitudinal measures of cognition in the Ts65Dn mouse: refining windows and defining modalities for therapeutic intervention in Down syndrome. Exp. Neurol. 279, 40– 56 10.1016/j.expneurol.2016.02.005 26854932 PMC5716476 · DOI
  77. [77]Rueda N., Flórez J. and Martínez-Cué C. (2008) Chronic pentylenetetrazole but not donepezil treatment rescues spatial cognition in Ts65Dn mice, a model for Down syndrome. Neurosci. Lett. 433, 22– 27 10.1016/j.neulet.2007.12.039 18226451 · DOI
  78. [79]Pereira P.L. et al. (2009) A new mouse model for the trisomy of the Abcg1–U2af1 region reveals the complexity of the combinatorial genetic code of down syndrome. Hum. Mol. Genet. 18, 4756– 4769 10.1093/hmg/ddp438 19783846 PMC2778371 · DOI
  79. [80]Villar A.J. et al. (2005) Identification and characterization of a new Down syndrome model, Ts[Rb(12.1716)]2Cje, resulting from a spontaneous Robertsonian fusion between T(1716)65Dn and mouseChromosome 12. Mamm. Genome 16, 79– 90 10.1007/s00335-004-2428-7 15859352 · DOI
  80. [81]Ahmed, Md. M. et al. (2013) Protein profiles in Tc1 mice implicate novel pathway perturbations in the Down syndrome brain. Hum. Mol. Genet. 22, 1709– 1724 10.1093/hmg/ddt017 23349361 PMC3613160 · DOI
  81. [82]Yu T. et al. (2010) A mouse model of Down syndrome trisomic for all human chromosome 21 syntenic regions. Hum. Mol. Genet. 19, 2780– 2791 10.1093/hmg/ddq179 20442137 PMC2893810 · DOI
  82. [83]Rueda N., Flórez J. and Martínez-Cué C. (2012) Mouse models of down syndrome as a tool to unravel the causes of mental disabilities. Neural Plast. 2012, 584071 10.1155/2012/584071 22685678 PMC3364589 · DOI · Paper page
  83. [85]Vicari S. (2006) Motor development and neuropsychological patterns in persons with Down syndrome. Behav. Genet. 36, 355– 364 10.1007/s10519-006-9057-8 16505965 · DOI
  84. [86]Costanzo F. et al. (2013) Executive functions in intellectual disabilities: a comparison between Williams syndrome and Down syndrome. Res. Dev. Disabil. 34, 1770– 1780 10.1016/j.ridd.2013.01.024 23501586 · DOI · Paper page
  85. [87]Chapman R. and Hesketh L. (2000) Behavioral phenotype of individuals with Down syndrome. Ment. Retard. Dev. D R 10.1002/1098-2779(2000)6:2<84::AID-MRDD2>3.0.CO;2-P 10899801 · DOI
  86. [88]Reeves R.H. et al. (1995) A mouse model for Down syndrome exhibits learning and behaviour deficits. Nat. Genet. 11, 177– 184 10.1038/ng1095-177 7550346 · DOI · Paper page
  87. [89]Escorihuela R.M. et al. (1998) Impaired short- and long-term memory in Ts65Dn mice, a model for Down syndrome. Neurosci. Lett. 247, 171– 174 10.1016/S0304-3940(98)00317-6 9655620 · DOI
  88. [90]Holtzman D.M. et al. (1996) Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome. Proc. Natl. Acad. Sci. U.S.A. 93, 13333– 13338 10.1073/pnas.93.23.13333 8917591 PMC24093 · DOI · Paper page
  89. [91]Moran T.H. et al. (2002) The effects of piracetam on cognitive performance in a mouse model of Down’s syndrome. Physiol. Behav. 77, 403– 409 10.1016/S0031-9384(02)00873-9 12419416 · DOI
  90. [92]Sago H. et al. (2000) Genetic dissection of region associated with behavioral abnormalities in mouse models for Down syndrome. Pediatr. Res. 48, 606– 613 10.1203/00006450-200011000-00009 11044479 · DOI
  91. [94]Hunter C.L., Bimonte H.A. and Granholm A.-C.E. (2003) Behavioral comparison of 4 and 6 month-old Ts65Dn mice: Age-related impairments in working and reference memory. Behav. Brain Res. 138, 121– 131 10.1016/S0166-4328(02)00275-9 12527443 · DOI
  92. [95]Fernandez F. et al. (2007) Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nat. Neurosci. 10, 411– 413 10.1038/nn1860 17322876 · DOI
  93. [96]Colas D. et al. (2013) Short‐term treatment with the GABAA receptor antagonist pentylenetetrazole produces a sustained pro‐cognitive benefit in a mouse model of Down’s syndrome. Br. J. Pharmacol. 169, 963– 973 10.1111/bph.12169 23489250 PMC3696321 · DOI
  94. [97]Souza F.M., de Busquet S., Blatner N., Maclean K.N. and Restrepo D. (2011) Galantamine improves olfactory learning in the Ts65Dn mouse model of Down syndrome. Sci. Rep. 1, 137 10.1038/srep00137 22355654 PMC3216618 · DOI
  95. [98]Demas G.E., Nelson R.J., Krueger B.K. and Yarowsky P.J. (1998) Impaired spatial working and reference memory in segmental trisomy (Ts65Dn) mice. Behav. Brain Res. 90, 199– 201 10.1016/S0166-4328(97)00116-2 9521551 · DOI
  96. [99]Martínez-Cué C. et al. (1999) A murine model for Down syndrome shows reduced responsiveness to pain. Neuroreport 10, 1119– 1122 10.1097/00001756-199904060-00039 10321494 · DOI
  97. [100]Costa A.C.S., Walsh K. and Davisson M.T. (1999) Motor dysfunction in a mouse model for Down syndrome. Physiol. Behav. 68, 211– 220 10.1016/S0031-9384(99)00178-X 10627083 · DOI
  98. [101]Roubertoux P.L. et al. (2017) Differential brain, cognitive and motor profiles associated with partial trisomy. Modeling Down syndrome in mice. Behav. Genet. 47, 305– 322 10.1007/s10519-017-9835-5 28204906 · DOI
  99. [102]Glass T.J. and Connor N.P. (2016) Digastric muscle phenotypes of the Ts65Dn mouse model of Down syndrome. PLoS ONE 11, e0158008 10.1371/journal.pone.0158008 27336944 PMC4919106 · DOI
  100. [103]Cisterna B., Costanzo M., Scherini E., Zancanaro C. and Malatesta M. (2013) Ultrastructural features of skeletal muscle in adult and aging Ts65Dn mice, a murine model of Down syndrome. Muscles Ligaments Tendons J. 3, 287– 294 24596692 PMC3940502
  101. [104]Aziz N.M. et al. (2019) Spatiotemporal development of spinal neuronal and glial populations in the Ts65Dn mouse model of Down syndrome. J. Neurodev. Disord. 11, 35 10.1186/s11689-019-9294-9 31839007 PMC6913030 · DOI · Paper page
  102. [105]Coyle J., Price D. and DeLong M. (1983) Alzheimer's disease: a disorder of cortical cholinergic innervation. Science 219, 1184– 1190 10.1126/science.6338589 6338589 · DOI
  103. [106]Kása P., Rakonczay Z. and Gulya K. (1997) The cholinergic system in Alzheimer’s disease. Prog. Neurobiol. 52, 511– 535 10.1016/S0301-0082(97)00028-2 9316159 · DOI
  104. [107]Whitehouse P.J., Price D.L., Clark A.W., Coyle J.T. and DeLong M.R. (1981) Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann. Neurol. 10, 122– 126 10.1002/ana.410100203 7283399 · DOI · Paper page
  105. [108]Velazquez R. et al. (2012) Perinatal choline supplementation improves spatial learning and increases cholinergic neuron density in the medial septal nucleus in the Ts65Dn mouse model of Down syndrome. Neurotoxicol. Teratol. 34, 383 10.1016/j.ntt.2012.05.047 · DOI
  106. [109]Powers B.E. et al. (2016) Attentional function and basal forebrain cholinergic neuron morphology during aging in the Ts65Dn mouse model of Down syndrome. Brain Struct Funct. 221, 4337– 4352 10.1007/s00429-015-1164-y 26719290 PMC4929047 · DOI
  107. [110]Kelley C.M. et al. (2013) Sex differences in the cholinergic basal forebrain in the Ts65Dn mouse model of Down syndrome and Alzheimer’s disease. Brain Pathol. 24, 33– 44 10.1111/bpa.12073 23802663 PMC4220609 · DOI
  108. [111]Cooper J.D. et al. (2001) Failed retrograde transport of NGF in a mouse model of Down’s syndrome: reversal of cholinergic neurodegenerative phenotypes following NGF infusion. Proc. Natl. Acad. Sci. U.S.A. 98, 10439– 10444 10.1073/pnas.181219298 11504920 PMC56979 · DOI · Paper page
  109. [112]Kelley C.M. et al. (2014) Maternal choline supplementation differentially alters the basal forebrain cholinergic system of young-adult Ts65Dn and disomic mice. J. Comp. Neurol. 522, 1390– 1410 10.1002/cne.23492 24178831 PMC3959592 · DOI
  110. [113]Alldred M.J. et al. (2018) CA1 pyramidal neuron gene expression mosaics in the Ts65Dn murine model of Down syndrome and Alzheimer’s disease following maternal choline supplementation. Hippocampus 28, 251– 268 10.1002/hipo.22832 29394516 PMC5874173 · DOI
  111. [114]Sil’kis I.G. (2019) Possible mechanisms of the complex effects of acetylcholine on theta activity, learning, and memory. Neurochem. J. 13, 121– 136 10.1134/S1819712419020119 · DOI
  112. [115]Contestabile A., Fila T., Bartesaghi R., Contestabile A. and Ciani E. (2006) Choline acetyltransferase activity at different ages in brain of Ts65Dn mice, an animal model for Down’s syndrome and related neurodegenerative diseases. J. Neurochem. 97, 515– 526 10.1111/j.1471-4159.2006.03769.x 16539660 · DOI
  113. [116]Colas D. et al. (2008) Sleep and EEG features in genetic models of Down syndrome. Neurobiol. Dis. 30, 1– 7 10.1016/j.nbd.2007.07.014 18282758 PMC4689324 · DOI
  114. [117]Heller H.C., Freeburn A., Finn D.P. and Munn R.G.K. (2020) Disordered phasic relationships between hippocampal place cells, theta, and gamma rhythms in the Ts65Dn mouse model of Down Syndrome. bioRxiv, 10.1101/2020.09.17.301432 · DOI
  115. [118]Colgin L.L. (2015) Do slow and fast gamma rhythms correspond to distinct functional states in the hippocampal network? Brain Res. 1621, 309– 315 10.1016/j.brainres.2015.01.005 25591484 PMC4499490 · DOI
  116. [119]Igarashi K.M., Lu L., Colgin L.L., Moser M.-B. and Moser E.I. (2014) Coordination of entorhinal-hippocampal ensemble activity during associative learning. Nature 510, 143– 147 10.1038/nature13162 24739966 · DOI
  117. [120]Colgin L.L. and Moser E.I. (2010) Gamma oscillations in the hippocampus. Physiology 25, 319– 329 10.1152/physiol.00021.2010 20940437 · DOI
  118. [121]Colgin L. et al. (2009) Frequency of gamma oscillations routes flow of information in the hippocampus. Nature 462, 353 10.1038/nature08573 19924214 · DOI
  119. [122]de San Martin J.Z. et al. (2020) Alterations of specific cortical GABAergic circuits underlie abnormal network activity in a mouse model of Down syndrome. eLife 9, e58731 10.7554/eLife.58731 32783810 PMC7481006 · DOI
  120. [123]Hernández-González S. et al. (2015) Altered distribution of hippocampal interneurons in the murine Down syndrome model Ts65Dn. Neurochem. Res. 40, 151– 164 10.1007/s11064-014-1479-8 25399236 · DOI · Paper page
  121. [124]Laurie D., Wisden W. and Seeburg P. (1992) The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development. J. Neurosci. 12, 4151– 4172 10.1523/JNEUROSCI.12-11-04151.1992 1331359 PMC6576006 · DOI
  122. [125]Fritschy J. and Mohler H. (1995) GABAA‐receptor heterogeneity in the adult rat brain: Differential regional and cellular distribution of seven major subunits. J. Comp. Neurol. 359, 154– 194 10.1002/cne.903590111 8557845 · DOI · Paper page
  123. [126]Vidal V. et al. (2018) Decreasing the expression of GABAA α5 subunit-containing receptors partially improves cognitive, electrophysiological, and morphological hippocampal defects in the Ts65Dn model of Down syndrome. Mol. Neurobiol. 55, 4745– 4762 10.1007/s12035-017-0675-3 28717969 · DOI
  124. [127]Baudry M., Bi X., Gall C. and Lynch G. (2011) The biochemistry of memory: The 26year journey of a ‘new and specific hypothesis’. Neurobiol. Learn. Mem. 95, 125– 133 10.1016/j.nlm.2010.11.015 21134478 PMC3042723 · DOI
  125. [130]Best T.K., Cramer N.P., Chakrabarti L., Haydar T.F. and Galdzicki Z. (2011) Dysfunctional hippocampal inhibition in the Ts65Dn mouse model of Down syndrome. Exp. Neurol. 233, 749– 757 10.1016/j.expneurol.2011.11.033 22178330 PMC4123861 · DOI
  126. [131]Siarey R.J. et al. (1999) Increased synaptic depression in the Ts65Dn mouse, a model for mental retardation in Down syndrome. Neuropharmacology 38, 1917– 1920 10.1016/S0028-3908(99)00083-0 10608287 · DOI · Paper page
  127. [132]Belichenko P.V. et al. (2009) Excitatory‐inhibitory relationship in the fascia dentata in the Ts65Dn mouse model of down syndrome. J. Comp. Neurol. 512, 453– 466 10.1002/cne.21895 19034952 PMC8480942 · DOI · Paper page
  128. [133]Mojabi F.S. et al. (2016) GABAergic hyperinnervation of dentate granule cells in the Ts65Dn mouse model of down syndrome: exploring the role of App. Hippocampus 26, 1641– 1654 10.1002/hipo.22664 27701794 · DOI
  129. [134]Kleschevnikov A.M. et al. (2011) Increased efficiency of the GABAA and GABAB receptor-mediated neurotransmission in the Ts65Dn mouse model of Down syndrome. Neurobiol. Dis. 45, 683– 691 10.1016/j.nbd.2011.10.009 22062771 PMC3259223 · DOI · Paper page
  130. [135]Duchon A. et al. (2020) Long‐lasting correction of in vivo LTP and cognitive deficits of mice modelling Down syndrome with an α5‐selective GABAA inverse agonist. Br. J. Pharmacol. 177, 1106– 1118 10.1111/bph.14903 31652355 PMC7042104 · DOI
  131. [136]Kirk I.J. (1998) Frequency modulation of hippocampal theta by the supramammillary nucleus, and other hypothalamo–hippocampal interactions: mechanisms and functional implications. Neurosci. Biobehav. Rev. 22, 291– 302 10.1016/S0149-7634(97)00015-8 9579319 · DOI
  132. [137]Kirk I. and McNaughton N. (1991) Supramammillary cell firing and hippocampal rhythmical slow activity. Neuroreport 2, 723– 725 10.1097/00001756-199111000-00023 1810464 · DOI
  133. [138]Kirk I.J. (1997) Supramammillary neural discharge patterns and hippocampal EEG. Brain Res. Bull. 42, 23– 26 10.1016/S0361-9230(96)00094-9 8978931 · DOI
  134. [139]Marin‐Padilla M. (1976) Pyramidal cell abnormalities in the motor cortex of a child with Down’s syndrome. A Golgi study. J. Comp. Neurol. 167, 63– 81 10.1002/cne.901670105 131810 · DOI · Paper page
  135. [140]Vukšić M., Petanjek Z., Rašin M.R. and Kostović I. (2002) Perinatal growth of prefrontal layer III pyramids in down syndrome. Pediatr. Neurol. 27, 36– 38 10.1016/S0887-8994(02)00380-6 12160971 · DOI
  136. [142]Vuksic M. et al. (2011) Unilateral entorhinal denervation leads to long-lasting dendritic alterations of mouse hippocampal granule cells. Exp. Neurol. 230, 176– 185 10.1016/j.expneurol.2011.04.011 21536031 · DOI
  137. [143]Shim K.S. and Lubec G. (2002) Drebrin, a dendritic spine protein, is manifold decreased in brains of patients with Alzheimer’s disease and Down syndrome. Neurosci. Lett. 324, 209– 212 10.1016/S0304-3940(02)00210-0 12009525 · DOI
  138. [144]Insausti A. et al. (1998) Hippocampal volume and neuronal number in Ts65Dn mice: a murine model of down syndrome. Neurosci. Lett. 253, 175– 178 10.1016/S0304-3940(98)00641-7 9792239 · DOI · Paper page
  139. [145]Carbonell J., Blasco-Ibáñez J.M., Crespo C., Nácher J. and Varea E. (2020) Piriform cortex alterations in the ts65dn model for down syndrome. Brain Res. 1747, 147031 10.1016/j.brainres.2020.147031 32726601 · DOI
  140. [146]Kurt M.A., Davies D.C., Kidd M., Dierssen M. and Flórez J. (2000) Synaptic deficit in the temporal cortex of partial trisomy 16 (Ts65Dn) mice. Brain Res. 858, 191– 197 10.1016/S0006-8993(00)01984-3 10700614 · DOI
  141. [147]Kurt M.A., Kafa M.I., Dierssen M. and Davies D.C. (2004) Deficits of neuronal density in CA1 and synaptic density in the dentate gyrus, CA3 and CA1, in a mouse model of Down syndrome. Brain Res. 1022, 101– 109 10.1016/j.brainres.2004.06.075 15353219 · DOI · Paper page
  142. [148]Contestabile A. et al. (2007) Cell cycle alteration and decreased cell proliferation in the hippocampal dentate gyrus and in the neocortical germinal matrix of fetuses with down syndrome and in Ts65Dn mice. Hippocampus 17, 665– 678 10.1002/hipo.20308 17546680 · DOI · Paper page
  143. [149]Masuda T. et al. (2012) Noradrenaline increases neural precursor cells derived from adult rat dentate gyrus through beta2 receptor. Prog. Neuropsychopharmacol. Biol. Psychiatry 36, 44– 51 10.1016/j.pnpbp.2011.08.019 21914456 · DOI
  144. [150]Emili M. et al. (2020) Neonatal therapy with clenbuterol and salmeterol restores spinogenesis and dendritic complexity in the dentate gyrus of the Ts65Dn model of Down syndrome. Neurobiol. Dis. 140, 104874 10.1016/j.nbd.2020.104874 32325119 · DOI
  145. [151]Bortolotto V. et al. (2019) Salmeterol, a β2 adrenergic agonist, promotes adult hippocampal neurogenesis in a region-specific manner. Front. Pharmacol. 10, 1000 10.3389/fphar.2019.01000 31572182 PMC6751403 · DOI
  146. [152]Chuluun B. et al. (2020) Suprachiasmatic lesions restore object recognition in Down syndrome model mice. Neurobiol. Sleep Circad. Rhythm 8, 100049 10.1016/j.nbscr.2020.100049 PMC7075983 32195448 · DOI
  147. [153]Fernandez F. et al. (2017) Young children with Down syndrome show normal development of circadian rhythms, but poor sleep efficiency: a cross-sectional study across the first 60 months of life. Sleep Med. 33, 134– 144 10.1016/j.sleep.2016.12.026 28449894 PMC5423393 · DOI
  148. [154]Lukowski A.F., Slonecker E.M. and Milojevich H.M. (2020) Sleep problems and recall memory in children with Down syndrome and typically developing controls. Res. Dev. Disabil. 96, 103512 10.1016/j.ridd.2019.103512 31743853 PMC7316139 · DOI
  149. [155]Horne R.S.C., Wijayaratne P., Nixon G.M. and Walter L.M. (2018) Sleep and sleep disordered breathing in children with Down syndrome: effects on behaviour, neurocognition and the cardiovascular system. Sleep Med. Rev. 44, 1– 11 10.1016/j.smrv.2018.11.002 30576943 · DOI
  150. [156]Bassell J.L., Phan H., Leu R., Kronk R. and Visootsak J. (2015) Sleep profiles in children with down syndrome. Am. J. Med. Genet. A 167, 1830– 1835 10.1002/ajmg.a.37096 PMC4515186 26105013 · DOI
  151. [158]Bina K.G., Rusak B. and Semba K. (1993) Localization of cholinergic neurons in the forebrain and brainstem that project to the suprachiasmatic nucleus of the hypothalamus in rat. J. Comp. Neurol. 335, 295– 307 10.1002/cne.903350212 8227520 · DOI
  152. [159]Bina K.G., Rusak B. and Semba K. (1997) Sources of p75-nerve growth factor receptor-like immunoreactivity in the rat suprachiasmatic nucleus. Neuroscience 77, 461– 472 10.1016/S0306-4522(96)00496-4 9472404 · DOI
  153. [160]Madeira M.D., Pereira P.A., Silva S.M., Cadete-Leite A. and Paula-Barbosa M.M. (2004) Basal forebrain neurons modulate the synthesis and expression of neuropeptides in the rat suprachiasmatic nucleus. Neuroscience 125, 889– 901 10.1016/j.neuroscience.2004.03.005 15120850 · DOI
  154. [161]Watts A.G., Swanson L.W. and Sanchez‐Watts G. (1987) Efferent projections of the suprachiasmatic nucleus: I. Studies using anterograde transport of Phaseolus vulgaris leucoagglutinin in the rat. J. Comp. Neurol. 258, 204– 229 10.1002/cne.902580204 3294923 · DOI
  155. [162]Ruby N.F. et al. (2010) Circadian locomotor rhythms are normal in Ts65Dn “Down Syndrome” mice and unaffected by pentylenetetrazole. J. Biol. Rhythm. 25, 63– 66 10.1177/0748730409356202 20075302 · DOI
  156. [163]Ruby N.F. et al. (2017) Scheduled feeding restores memory and modulates c-Fos expression in the suprachiasmatic nucleus and septohippocampal complex. Sci. Rep. 7, 6755 10.1038/s41598-017-06963-w 28754901 PMC5533780 · DOI
  157. [164]Ruby N.F. et al. (2013) Spatial memory and long-term object recognition are impaired by circadian arrhythmia and restored by the GABAA antagonist pentylenetetrazole. PLoS ONE 8, e72433 10.1371/journal.pone.0072433 24009680 PMC3756994 · DOI
  158. [165]Potier M.-C., Braudeau J., Dauphinot L. and Delatour B. (2014) Reducing GABAergic inhibition restores cognitive functions in a mouse model of Down syndrome. CNS Neurol. Disord. Drug Targets 13, 8– 15 10.2174/18715273113126660185 24152333 · DOI · Paper page
  159. [166]Best T.K., Siarey R.J. and Galdzicki Z. (2007) Ts65Dn, a mouse model of down syndrome, exhibits increased GABA B -induced potassium current. J. Neurophysiol. 97, 892– 900 10.1152/jn.00626.2006 17093127 · DOI
  160. [167]Zhong P. and Yan Z. (2004) Chronic antidepressant treatment alters serotonergic regulation of GABA transmission in prefrontal cortical pyramidal neurons. Neuroscience 129, 65– 73 10.1016/j.neuroscience.2004.06.072 15489029 · DOI · Paper page
  161. [169]Heinen M. et al. (2012) Adult-onset fluoxetine treatment does not improve behavioral impairments and may have adverse effects on the Ts65Dn mouse model of Down syndrome. Neural Plast. 2012, 467251 10.1155/2012/467251 22848851 PMC3405721 · DOI
  162. [170]Judge S.J., Ingram C.D. and Gartside S.E. (2004) GABA receptor modulation of 5-HT neuronal firing: characterization and effect of moderate in vivo variations in glucocorticoid levels. Neurochem. Int. 45, 1057– 1065 10.1016/j.neuint.2004.05.003 15337305 · DOI

Cited by

Sorted by citations

Authors
Freeburn, A., & Munn, R. G. K.
Affiliations
Ollscoil na Gaillimhe – University of Galway (IE)
Corresponding author
Munn, Robert Gordon Keith
ORCID
Munn, Robert Gordon Keith
Venue
Neuronal Signaling
Publisher
Portland Press Ltd.
Published
2021-03-12
Volume
5
Issue
1
Pages
NS20200011-NS20200011
ISSN
2059-6553 (ISSN-L)
DOI
10.1042/ns20200011
PMC
PMC7955101
OpenAlex
W3135150931
Cited by
37
References
7
Citations by year
2026: 1 · 2025: 3 · 2024: 28 · 2023: 1 · 2022: 4
FWCI
1.47
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuronal Signaling (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
Down syndrome, Ts65Dn mouse model, trisomy 16, learning and memory impairment, hippocampus, entorhinal cortex, spatial memory, hippocampal electrophysiology, hippocampal microstructure, basal forebrain, pharmacotherapy

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review