Abstract
Fragile X syndrome afflicts 1 in 2,500 individuals and is the leading heritable cause of mental retardation worldwide. The overriding clinical manifestation of this disease is mild to severe cognitive impairment. Age-dependent cognitive decline has been identified in Fragile X patients, although it has not been fully characterized nor examined in animal models. A Drosophila model of this disease has been shown to display phenotypes bearing similarity to Fragile X symptoms. Most notably, we previously identified naive courtship and memory deficits in young adults with this model that appear to be due to enhanced metabotropic glutamate receptor (mGluR) signaling. Herein we have examined age-related cognitive decline in the Drosophila Fragile X model and found an age-dependent loss of learning during training. We demonstrate that treatment with mGluR antagonists or lithium can prevent this age-dependent cognitive impairment. We also show that treatment with mGluR antagonists or lithium during development alone displays differential efficacy in its ability to rescue naive courtship, learning during training and memory in aged flies. Furthermore, we show that continuous treatment during aging effectively rescues all of these phenotypes. These results indicate that the Drosophila model recapitulates the age-dependent cognitive decline observed in humans. This places Fragile X in a category with several other diseases that result in age-dependent cognitive decline. This demonstrates a role for the Drosophila Fragile X Mental Retardation Protein (dFMR1) in neuronal physiology with regard to cognition during the aging process. Our results indicate that misregulation of mGluR activity may be causative of this age onset decline and strengthens the possibility that mGluR antagonists and lithium may be potential pharmacologic compounds for counteracting several Fragile X symptoms.
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References
Acharya JK, Labarca P, Delgado R, Jalink K, Zuker CS (1998) Synaptic defects and compensatory regulation of inositol metabolism in inositol polyphosphate 1-phosphatase mutants. Neuron 20:1219–1229
Bakker CE, Oostra BA (2003) Understanding fragile X syndrome: insights from animal models. Cytogenet Genome Res 100:111–123
Bastock MA (1955) The courtship of drosophila melanogaster. Behaviour 8:86–111
Bastock MA (1956) A gene mutation which changes a behavior pattern. Evolution 10:421–439
Bear MF, Huber KM, Warren ST (2004) The mGluR theory of fragile X mental retardation. Trends Neurosci 27:370–377
Berry-Kravis E, Abrams L, Coffey SM, Hall DA, Greco C, Gane LW, Grigsby J, Bourgeois JA, Finucane B, Jacquemont S, Brunberg JA, Zhang L, Lin J, Tassone F, Hagerman PJ, Hagerman RJ, Leehey MA (2007) Fragile X-associated tremor/ataxia syndrome: clinical features, genetics, and testing guidelines. Mov Disord 22:2018–2030 (quiz 2140)
Bolduc FV, Bell K, Cox H, Broadie KS, Tully T (2008) Excess protein synthesis in Drosophila fragile X mutants impairs long-term memory. Nat Neurosci 11:1143–1145
Brega AG, Goodrich G, Bennett RE, Hessl D, Engle K, Leehey MA, Bounds LS, Paulich MJ, Hagerman RJ, Hagerman PJ, Cogswell JB, Tassone F, Reynolds A, Kooken R, Kenny M, Grigsby J (2008) The primary cognitive deficit among males with fragile X-associated tremor/ataxia syndrome (FXTAS) is a dysexecutive syndrome. J Clin Exp Neuropsychol 31:1–17
Chuang SC, Zhao W, Bauchwitz R, Yan Q, Bianchi R, Wong RK (2005) Prolonged epileptiform discharges induced by altered group I metabotropic glutamate receptor-mediated synaptic responses in hippocampal slices of a fragile X mouse model. J Neurosci 25:8048–8055
Cornish KM, Li L, Kogan CS, Jacquemont S, Turk J, Dalton A, Hagerman RJ, Hagerman PJ (2008) Age-dependent cognitive changes in carriers of the fragile X syndrome. Cortex 44:628–636
Cornish KM, Kogan CS, Li L, Turk J, Jacquemont S, Hagerman RJ (2009) Lifespan changes in working memory in fragile X premutation males. Brain Cogn 69:551–558
Crawford DC, Meadows KL, Newman JL, Taft LF, Scott E, Leslie M, Shubek L, Holmgreen P, Yeargin-Allsopp M, Boyle C, Sherman SL (2002) Prevalence of the fragile X syndrome in African-Americans. Am J Med Genet 110:226–233
Dockendorff TC, Su HS, McBride SM, Yang Z, Choi CH, Siwicki KK, Sehgal A, Jongens TA (2002) Drosophila lacking dfmr1 activity show defects in circadian output and fail to maintain courtship interest. Neuron 34:973–984
Dolen G, Osterweil E, Rao BS, Smith GB, Auerbach BD, Chattarji S, Bear MF (2007) Correction of fragile X syndrome in mice. Neuron 56:955–962
Ehninger D, Li W, Fox K, Stryker MP, Silva AJ (2008) Reversing neurodevelopmental disorders in adults. Neuron 60:950–960
Galvez R, Greenough WT (2005) Sequence of abnormal dendritic spine development in primary somatosensory cortex of a mouse model of the fragile X mental retardation syndrome. Am J Med Genet A 135:155–160
Griffith LC, Verselis LM, Aitken KM, Kyriacou CP, Danho W, Greenspan RJ (1993) Inhibition of calcium/calmodulin-dependent protein kinase in Drosophila disrupts behavioral plasticity. Neuron 10:501–509
Hagerman RJ, Hagerman PJ (2002) Fragile X syndrome: diagnosis, treatment, and research, 3rd edn. John Hopkins University Press, Baltimore, MD, USA
Hagerman RJ, Schreiner RA, Kemper MB, Wittenberger MD, Zahn B, Habicht K (1989) Longitudinal IQ changes in fragile X males. Am J Med Genet 33:513–518
Hall JC (1994) The mating of a fly. Science 264:1702–1714
Hallcher LM, Sherman WR (1980) The effects of lithium ion and other agents on the activity of myo-inositol-1-phosphatase from bovine brain. J Biol Chem 255:10896–10901
Hatton DD, Sideris J, Skinner M, Mankowski J, Bailey DB Jr, Roberts J, Mirrett P (2006) Autistic behavior in children with fragile X syndrome: prevalence, stability, and the impact of FMRP. Am J Med Genet A 140A:1804–1813
Hay DA (1994) Does IQ decline with age in fragile-X? A methodological critique. Am J Med Genet 51:358–363
Heriche JK, Ang D, Bier E, O’Farrell PH (2003) Involvement of an SCFSlmb complex in timely elimination of E2F upon initiation of DNA replication in drosophila. BMC Genet 4:9
Jacquemont S, Hagerman RJ, Hagerman PJ, Leehey MA (2007) Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1. Lancet Neurol 6:45–55
Jaffe AB, Jongens TA (2001) Structure-specific abnormalities associated with mutations in a DNA replication accessory factor in drosophila. Dev Biol 230:161–176
Joiner Ml A, Griffith LC (1997) CaM kinase II and visual input modulate memory formation in the neuronal circuit controlling courtship conditioning. J Neurosci 17:9384–9391
Kamyshev NG, Iliadi KG, Bragina JV (1999) Drosophila conditioned courtship: two ways of testing memory. Learn Mem 6:1–20
Kane NS, Robichon A, Dickinson JA, Greenspan RJ (1997) Learning without performance in PKC-deficient drosophila. Neuron 18:307–314
Kenneson A, Zhang F, Hagedorn CH, Warren ST (2001) Reduced FMRP and increased FMR1 transcription is proportionally associated with CGG repeat number in intermediate-length and permutation carriers. Hum Mol Genet 10:1449–1454
Klein PS, Melton DA (1996) A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci USA 93:8455–8459
Landis SC (1976) Rat sympathetic neurons and cardiac myocytes developing in microcultures: correlation of the fine structure of endings with neurotransmitter function in single neurons. Proc Natl Acad Sci USA 73:4220–4224
Larson J, Jessen RE, Kim D, Fine AK, du Hoffmann J (2005) Age-dependent and selective impairment of long-term potentiation in the anterior piriform cortex of mice lacking the fragile X mental retardation protein. J Neurosci 25:9460–9469
McBride SM, Giuliani G, Choi C, Krause P, Correale D, Watson K, Baker G, Siwicki KK (1999) Mushroom body ablation impairs short-term memory and long-term memory of courtship conditioning in drosophila melanogaster. Neuron 24:967–977
McBride SM, Choi CH, Wang Y, Liebelt D, Braunstein E, Ferreiro D, Sehgal A, Siwicki KK, Dockendorff TC, Nguyen HT, McDonald TV, Jongens TA (2005) Pharmacological rescue of synaptic plasticity, courtship behavior, and mushroom body defects in a drosophila model of fragile X syndrome. Neuron 45:753–764
Michel CI, Kraft R, Restifo LL (2004) Defective neuronal development in the mushroom bodies of drosophila fragile X mental retardation 1 mutants. J Neurosci 24:5798–5809
Morales J, Hiesinger PR, Schroeder AJ, Kume K, Verstreken P, Jackson FR, Nelson DL, Hassan BA (2002) Drosophila fragile X protein, DFXR, regulates neuronal morphology and function in the brain. Neuron 34:961–972
O’Donnell WT, Warren ST (2002) A decade of molecular studies of fragile X syndrome. Annu Rev Neurosci 25:315–338
Orgad S, Rosenfeld G, Greenspan RJ, Segal D (2000) Courtless, the Drosophila UBC7 homolog, is involved in male courtship behavior and spermatogenesis. Genetics 155:1267–1280
Palladino MJ, Keegan LP, O’Connell MA, Reenan RA (2000) A-to-I pre-mRNA editing in drosophila is primarily involved in adult nervous system function and integrity. Cell 102:437–449
Pan L, Woodruff E 3rd, Liang P, Broadie K (2008) Mechanistic relationships between drosophila fragile X mental retardation protein and metabotropic glutamate receptor A signaling. Mol Cell Neurosci 37:747–760
Pascual A, Preat T (2001) Localization of long-term memory within the drosophila mushroom body. Science 294:1115–1117
Raymond FL, Tarpey P (2006) The genetics of mental retardation. Hum Mol Genet 15:R110–R116 (Spec No 2)
Restifo LL (2005) Mental retardation genes in drosophila: new approaches to understanding and treating developmental brain disorders. Ment Retard Dev Disabil Res Rev 11:286–294
Savvateeva E, Popov A, Kamyshev N, Bragina J, Heisenberg M, Senitz D, Kornhuber J, Riederer P (2000) Age-dependent memory loss, synaptic pathology and altered brain plasticity in the drosophila mutant cardinal accumulating 3-hydroxykynurenine. J Neural Transm 107:581–601
Siegel RW, Hall JC (1979) Conditioned responses in courtship behavior of normal and mutant drosophila. Proc Natl Acad Sci USA 76:3430–3434
Sokal RR, Rohlf FJ (1995) Biometry: the principles and practice of statistics in biological research, 3rd edn. W.H. Freeman and Co, New York
Spieth HT (1974) Courtship behavior in drosophila. Annu Rev Entomol 19:385–405
Sturtevant AH (1915) Experiments on sex recognition and the problem of sexual selection in drosophila. J Anim Behav 5:351–366
van Swinderen B, Hall JC (1995) Analysis of conditioned courtship in dusky-Andante rhythm mutants of drosophila. Learn Mem 2:49–61
Villella A, Hall JC (1996) Courtship anomalies caused by double sex mutations in drosophila melanogaster. Genetics 143:331–344
Walsh CA, Morrow EM, Rubenstein JL (2008) Autism and brain development. Cell 135:396–400
Wan L, Dockendorff TC, Jongens TA, Dreyfuss G (2000) Characterization of dFMR1, a drosophila melanogaster homolog of the fragile X mental retardation protein. Mol Cell Biol 20:8536–8547
Wright-Talamante C, Cheema A, Riddle JE, Luckey DW, Taylor AK, Hagerman RJ (1996) A controlled study of longitudinal IQ changes in females and males with fragile X syndrome. Am J Med Genet 64:350–355
Yan QJ, Rammal M, Tranfaglia M, Bauchwitz RP (2005) Suppression of two major Fragile X syndrome mouse model phenotypes by the mGluR5 antagonist MPEP. Neuropharmacology 49:1053–1066
Zarnescu DC, Jin P, Betschinger J, Nakamoto M, Wang Y, Dockendorff TC, Feng Y, Jongens TA, Sisson JC, Knoblich JA, Warren ST, Moses K (2005) Fragile X protein functions with lgl and the par complex in flies and mice. Dev Cell 8:43–52
Zars T, Fischer M, Schulz R, Heisenberg M (2000) Localization of a short-term memory in drosophila. Science 288:672–675
Zhang YQ, Bailey AM, Matthies HJ, Renden RB, Smith MA, Speese SD, Rubin GM, Broadie K (2001) Drosophila fragile X-related gene regulates the MAP1B homolog Futsch to control synaptic structure and function. Cell 107:591–603
Acknowledgments
We received helpful input on the experiments contained in this manuscript from communications with Mike Tranfaglia, Joseph Hinchey, Sean Campbell, Kathleen Siwicki, and John Jenkins. We are grateful to Randi Hagerman and Evan Braunstein for critically reading the manuscript. Technical assistance was provided by Charles Smith, Oliver Schipper and Edward Carlin. Funding for this work came from grants from the FRAXA Research Foundation to S.M.J.M, C.H.C., and T.A.J. A Medical Scientist Training Program grant through Albert Einstein College of Medicine supported S.M.J.M. This work was also funded by a grant from Autism Speaks to T.V.M and S.M.J.M., as well as funding to E.K. from The National Fragile X Foundation. T.A.J. received a NIH grant (NS046573) to support this work.
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10522_2009_9259_MOESM1_ESM.jpg
Supplemental Fig. 1. Comparison of naive courtship in young (5 days post eclosion) versus old (20 days post eclosion) flies. The position of the CT or M is indicative of the point at which the group was on the particular food. The first letter indicates the food type that the larvae grew up on, and the second letter indicates the food type that the adults fly was placed on within 4 h of eclosion for 4 days in the case of testing at day 5 and 19 days in the case of testing at day 20. (CT) refers to control food and (M) indicates food with 8.6 μM MPEP. Mean CIs (±SEM) are plotted; Ns are indicated above each bar for all groups. Black bars indicate (CT-CT) WT males (dFMR13 +wild type rescue fragment); hatched bars indicate (CT–CT) FS males (dFMR13 + frame shifted rescue fragment); blue bars indicate (M–M) WT males; open bars indicate (M–M) FS males; gray bars indicate (M–CT) WT males; green bars indicate (M–CT) FS males; yellow bars indicate (CT–M) WT males; red bars indicate (CT–M) FS males. For this comparison, the 20 day data is repeated from Fig. 1 and the 5 day data is repeated from McBride et al. 2005. (JPG 88 kb)
10522_2009_9259_MOESM2_ESM.jpg
Supplemental Fig. 2. The binning of naive courtship of dfmr1 flies 20 days post eclosion. The position of the CT or M is indicative of the point at which the group was on the particular food. The first letter indicates the food type that the larvae grew up on, and the second letter indicates the food type that the adults fly was placed on within 4 h of eclosion for 19 days and the flies were tested at day 20. (CT) refers to control food and (M) indicates food with 86 μM MPEP. Black bars (CT–CT) WT (dFMR13 + wild type rescue fragment); hatched bars (CT–M) WT; blue bars (CT–CT) FS (dFMR13 + frame shifted rescue fragment); open bars (CT–M) FS; gray bars (M–M) WT; green bars (M–CT) WT; yellow bars (M–M) FS; red (M–CT) FS. The quality of courtship that was performed by naive males was further analyzed by binning the number of males that advanced to particular phases of courtship for each genotype and pharmacologic treatment that was shown in Fig. 1 (a–d). The categories are as follows: (Orient/Follow) indicates the percentage of flies that reached the stages of orienting toward the virgin female target and following her; (Tap/wing ext) indicates the percentage of flies that reach the stage of tapping the female abdomen with a foreleg and extending and vibrating a wing; (lick/copull att) indicates the percentage of male flies that licked the female abdomen and attempted copulation. For all FS flies that were exposed to MPEP in adulthood or both development and adulthood, a higher percentage of flies progressed to the more advanced stages of courtship (tapping and wing extension) relative to the (CT–CT) FS flies. This demonstrated that MPEP treatment during development and development or in adulthood improved the quality of naive courtship behavior in FS flies. The (CT–CT) FS and (M–CT) FS flies had the lowest percentage of flies that advanced to later stages of courtship compared to all other groups. In fact there was a significant decrease in only (CT–CT) FS flies and (M–CT) FS flies in progressing to the later steps of courtship (tapping and wing extension) when compared to CT–CT WT flies, P < 0.05. (JPG 109 kb)
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Choi, C.H., McBride, S.M.J., Schoenfeld, B.P. et al. Age-dependent cognitive impairment in a Drosophila Fragile X model and its pharmacological rescue. Biogerontology 11, 347–362 (2010). https://doi.org/10.1007/s10522-009-9259-6
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DOI: https://doi.org/10.1007/s10522-009-9259-6