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Sex-Dependent Sensory Phenotypes and Related Transcriptomic Expression Profiles Are Differentially Affected by Angelman Syndrome

  • Lee Koyavski
  • Julia Panov
  • Lilach Simchi
  • Prudhvi Raj Rayi
  • Lital Sharvit
  • Yonatan Feuermann
  • Hanoch KaphzanEmail author
Article

Abstract

Angelman syndrome (AS) is a genetic disorder which entails autism, intellectual disability, lack of speech, motor deficits, and seizure susceptibility. It is caused by the lack of UBE3A protein expression, which is an E3-ubiquitin ligase. Despite AS equal prevalence in males and females, not much data on how sex affects the syndrome was reported. In the herein study, we thoroughly characterized many behavioral phenotypes of AS mice. The behavioral data acquired was analyzed with respect to sex. In addition, we generated a new mRNA sequencing dataset. We analyzed the coding transcriptome expression profiles with respect to the effects of genotype and sex observed in the behavioral phenotypes. We identified several neurobehavioral aspects, especially sensory perception, where AS mice either lack the male-to-female differences observed in wild-type littermates or even show opposed differences. However, motor phenotypes did not show male-to-female variation between wild-type (WT) and AS mice. In addition, by utilizing the mRNA sequencing, we identified genes and isoforms with expression profiles that mirror the sensory perception results. These genes are differentially regulated in the two sexes with inverse expression profiles in AS mice compared to WT littermates. Some of these are known pain-related and estrogen-dependent genes. The observed differences in sex-dependent neurobehavioral phenotypes and the differential transcriptome expression profiles in AS mice strengthen the evidence for molecular cross talk between Ube3a protein and sex hormone receptors or their elicited pathways. These interactions are essential for understanding Ube3a deletion effects, beyond its E3-ligase activity.

Keywords

Angelman syndrome Ube3a Sex Behavioral phenotypes Transcriptome Bioinformatics analyses 

Abbreviations

AS

Angelman syndrome

WT

wild type

CFC

contextual fear conditioning

MWM

Morris water maze

OFA

open-field arena

SOD

simple odor discrimination

SROI

sex-related opposite interaction

CTD

Comparative Toxicogenomics Database

Notes

Acknowledgements

We thank the Tauber Bioinformatics Research Center at the University of Haifa for their help and assistance in the bioinformatics analyses.

Author’s contributions

HK initiated the study. LK and HK designed the behavioral experiments. LK performed the experiments and supplied the data for analysis. PRR, LK, and HK analyzed the behavioral data. LS (Simchi) and LS (Sharvit) produced the biological material for RNA sequencing. JP, YF, and HK performed the bioinformatics analyses. LK, JP, YF, PRR, and HK wrote the manuscript.

Funding

This work was supported by personal grants from the Angelman Syndrome Foundation and by the Israel Science Foundation, Grant Number 287/15.

Compliance with Ethical Standards

Ethical Approval

All procedures were performed in strict accordance with the University of Haifa regulations and the US National Institutes of Health guidelines (NIH publication number 8023). All experiments and breeding protocols were approved by the animal welfare committee of the University of Haifa and the Israeli ministry of health.

Conflict of Interest

The authors declare that they have no conflict of interest.

Consent for Publication

Not applicable.

Supplementary material

12035_2019_1503_MOESM1_ESM.docx (333 kb)
ESM 1 (DOCX 332 kb)

References

  1. 1.
    Williams CA, Beaudet AL, Clayton-Smith J, Knoll JH, Kyllerman M, Laan LA et al (2006) Angelman syndrome 2005: updated consensus for diagnostic criteria. Am J Med Genet A 140:413–418CrossRefGoogle Scholar
  2. 2.
    Jiang YHYH, Armstrong D, Albrecht U, Atkins CMCM, Noebels JLJL, Eichele G et al (1998) Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron 21:799–811.  https://doi.org/10.1016/S0896-6273(00)80596-6 CrossRefPubMedGoogle Scholar
  3. 3.
    Miura K, Kishino T, Li E, Webber H, Dikkes P, Holmes GL et al (2002) Neurobehavioral and electroencephalographic abnormalities in Ube3a maternal-deficient mice. Neurobiol Dis 9:149–159CrossRefGoogle Scholar
  4. 4.
    van Woerden GM, Harris KD, Hojjati MR, Gustin RM, Qiu S, de Avila Freire R et al (2007) Rescue of neurological deficits in a mouse model for Angelman syndrome by reduction of alphaCaMKII inhibitory phosphorylation. Nat Neurosci 10:280–282.  https://doi.org/10.1038/nn1845 CrossRefPubMedGoogle Scholar
  5. 5.
    Kishino T, Lalande M, Wagstaff J (1997) UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet 15:70–73.  https://doi.org/10.1038/ng0197-70 CrossRefPubMedGoogle Scholar
  6. 6.
    Matsuura T, Sutcliffe JSSJS, Fang P, Galjaard R-JJRJ, Jiang YHYH, Benton CSSCS et al (1997) De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nat Genet 15:74–77.  https://doi.org/10.1038/ng0197-74 CrossRefPubMedGoogle Scholar
  7. 7.
    Laan LA, den Boer AT, Hennekam RC, Renier WO, Brouwer OF (1996) Angelman syndrome in adulthood. Am J Med Genet 66:356–360.  https://doi.org/10.1002/(SICI)1096-8628(19961218)66:3<356::AID-AJMG21>3.0.CO;2-K CrossRefPubMedGoogle Scholar
  8. 8.
    Dan B (2009) Angelman syndrome: current understanding and research prospects. Epilepsia 50:2331–2339.  https://doi.org/10.1111/j.1528-1167.2009.02311.x CrossRefPubMedGoogle Scholar
  9. 9.
    Sidorov MS, Judson MC, Kim H, Rougie M, Ferrer AI, Nikolova VD et al (2018) Enhanced Operant extinction and prefrontal excitability in a mouse model of Angelman syndrome. J Neurosci 38:2671–2682.  https://doi.org/10.1523/JNEUROSCI.2828-17.2018 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Huang H-S, Burns AJ, Nonneman RJ, Baker LK, Riddick NV, Nikolova VD et al (2013) Behavioral deficits in an Angelman syndrome model: effects of genetic background and age. Behav Brain Res 243:79–90.  https://doi.org/10.1016/j.bbr.2012.12.052 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Born HA, Dao AT, Levine AT, Lee WL, Mehta NM, Mehra S et al (2017) Strain-dependence of the Angelman Syndrome phenotypes in Ube3a maternal deficiency mice. Sci Rep 7:1–15.  https://doi.org/10.1038/s41598-017-08825-x CrossRefGoogle Scholar
  12. 12.
    Wise EA, Price DD, Myers CD, Heft MW, Robinson ME (2002) Gender role expectations of pain: relationship to experimental pain perception. Pain 96:335–342 http://www.ncbi.nlm.nih.gov/pubmed/11973007 Accessed 1 Sep 2016CrossRefGoogle Scholar
  13. 13.
    Frick KM, Burlingame LA, Arters JA, Berger-Sweeney J (2000) Reference memory, anxiety and estrous cyclicity in C57BL/6NIA mice are affected by age and sex. Neuroscience 95:293–307 http://www.ncbi.nlm.nih.gov/pubmed/10619486 Accessed 6 Jul 2016.CrossRefGoogle Scholar
  14. 14.
    Sonzogni M, Wallaard I, Santos SS, Kingma J, du Mee D, van Woerden GM et al (2018) A behavioral test battery for mouse models of Angelman syndrome: a powerful tool for testing drugs and novel Ube3a mutants. Mol Autism 9:47.  https://doi.org/10.1186/s13229-018-0231-7 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kaphzan H, Hernandez P, Jung JI, Cowansage KK, Deinhardt K, Chao MV et al (2012) Reversal of impaired hippocampal long-term potentiation and contextual fear memory deficits in angelman syndrome model mice by ErbB inhibitors. Biol Psychiatry 72:182–190CrossRefGoogle Scholar
  16. 16.
    Santini E, Turner KL, Ramaraj AB, Murphy MP, Klann E, Kaphzan H (2015) Mitochondrial superoxide contributes to hippocampal synaptic dysfunction and memory deficits in Angelman syndrome Model Mice. J Neurosci 35:16213–16220.  https://doi.org/10.1523/JNEUROSCI.2246-15.2015 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Jiang Y-H, Pan Y, Zhu L, Landa L, Yoo J, Spencer C et al (2010) Altered ultrasonic vocalization and impaired learning and memory in Angelman syndrome mouse model with a large maternal deletion from Ube3a to Gabrb3. PLoS One 5:e12278.  https://doi.org/10.1371/journal.pone.0012278 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Marks HE, Hobbs SH (1972) Changes in stimulus reactivity following gonadectomy in male and female rats of different ages. Physiol Behav 8:1113–1119 http://www.ncbi.nlm.nih.gov/pubmed/5074025 Accessed 9 Apr 2017.CrossRefGoogle Scholar
  19. 19.
    Beatty WW, Beatty PA (1970) Hormonal determinants of sex differences in avoidance behavior and reactivity to electric shock in the rat. J Comp Physiol Psychol 73:446–455 http://www.ncbi.nlm.nih.gov/pubmed/5514680 Accessed 9 Apr 2017CrossRefGoogle Scholar
  20. 20.
    Daviu N, Andero R, Armario A, Nadal R (2014) Sex differences in the behavioural and hypothalamic–pituitary–adrenal response to contextual fear conditioning in rats. Horm Behav 66:713–723.  https://doi.org/10.1016/j.yhbeh.2014.09.015 CrossRefPubMedGoogle Scholar
  21. 21.
    Frick KM, Gresack JE (2003) Sex differences in the behavioral response to spatial and object novelty in adult C57BL/6 mice. Behav Neurosci 117:1283–1291.  https://doi.org/10.1037/0735-7044.117.6.1283 CrossRefPubMedGoogle Scholar
  22. 22.
    Barker GRI, Warburton EC (2011) When is the hippocampus involved in recognition memory? J Neurosci 31:10721–10731.  https://doi.org/10.1523/JNEUROSCI.6413-10.2011 CrossRefPubMedGoogle Scholar
  23. 23.
    Broadbent NJ, Gaskin S, Squire LR, Clark RE (2010) Object recognition memory and the rodent hippocampus. Learn Mem 17:5–11.  https://doi.org/10.1101/lm.1650110 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Godavarthi SK, Sharma A, Jana NR (2014) Reversal of reduced parvalbumin neurons in hippocampus and amygdala of Angelman syndrome model mice by chronic treatment of fluoxetine. J Neurochem 130:444–454.  https://doi.org/10.1111/jnc.12726 CrossRefPubMedGoogle Scholar
  25. 25.
    Barker GRI, Bird F, Alexander V, Warburton EC (2007) Recognition memory for objects, place, and temporal order: a disconnection analysis of the role of the medial prefrontal cortex and perirhinal cortex. J Neurosci 27:2948–2957.  https://doi.org/10.1523/JNEUROSCI.5289-06.2007 CrossRefPubMedGoogle Scholar
  26. 26.
    Antunes M, Biala G (2012) The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process 13:93–110.  https://doi.org/10.1007/s10339-011-0430-z CrossRefPubMedGoogle Scholar
  27. 27.
    Cigrang M, Vogel E, Misslin R (1986) Reduction of neophobia in mice following lesions of the caudate-putamen. Physiol Behav 36:25–28 http://www.ncbi.nlm.nih.gov/pubmed/3952181 Accessed 1 Sep 2016CrossRefGoogle Scholar
  28. 28.
    Karlsson SA, Haziri K, Hansson E, Kettunen P, Westberg L (2015) Effects of sex and gonadectomy on social investigation and social recognition in mice. BMC Neurosci 16:83.  https://doi.org/10.1186/s12868-015-0221-z CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Feinberg LM, Allen TA, Ly D, Fortin NJ (2012) Recognition memory for social and non-social odors: differential effects of neurotoxic lesions to the hippocampus and perirhinal cortex. Neurobiol Learn Mem 97:7–16.  https://doi.org/10.1016/j.nlm.2011.08.008 CrossRefPubMedGoogle Scholar
  30. 30.
    Rogers SJ, Hepburn S, Wehner E (2003) Parent reports of sensory symptoms in toddlers with autism and those with other developmental disorders. J Autism Dev Disord 33:631–642 http://www.ncbi.nlm.nih.gov/pubmed/14714932 Accessed 1 Sep 2016CrossRefGoogle Scholar
  31. 31.
    Brewer WJ, Brereton A, Tonge BJ (2008) Dissociation of age and ability on a visual analogue of the University of Pennsylvania Smell Identification Test in children with autism. Res Autism Spectr Disord 2:612–620CrossRefGoogle Scholar
  32. 32.
    May T, Brewer WJ, Rinehart NJ, Enticott PG, Brereton AV, Tonge BJ (2011) Differential olfactory identification in children with autism and Asperger’s disorder: a comparative and longitudinal study. J Autism Dev Disord 41:837–847.  https://doi.org/10.1007/s10803-010-1101-0 CrossRefPubMedGoogle Scholar
  33. 33.
    Ergorul C, Eichenbaum H (2004) The hippocampus and memory for “what,” “where,” and “when”. Learn Mem 11:397–405.  https://doi.org/10.1101/lm.73304 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Murphy C, Jernigan TL, Fennema-Notestine C (2003) Left hippocampal volume loss in Alzheimer’s disease is reflected in performance on odor identification: a structural MRI study. J Int Neuropsychol Soc 9:459–471.  https://doi.org/10.1017/S1355617703930116 CrossRefPubMedGoogle Scholar
  35. 35.
    Cerf-Ducastel B, Murphy C, Cerf-Ducastel B, Murphy C, Murphy C (2006) Neural substrates of cross-modal olfactory recognition memory: an fMRI study. NeuroImage 31:386–396.  https://doi.org/10.1016/j.neuroimage.2005.11.009 CrossRefPubMedGoogle Scholar
  36. 36.
    Wiesenfeld-Hallin Z (2005) Sex differences in pain perception. Gend Med 2:137–145 http://www.ncbi.nlm.nih.gov/pubmed/16290886 Accessed 1 Sep 2016CrossRefGoogle Scholar
  37. 37.
    Robinson ME, Riley JL, Myers CD, Papas RK, Wise EA, Waxenberg LB et al (2001) Gender role expectations of pain: relationship to sex differences in pain. J Pain 2:251–257.  https://doi.org/10.1054/jpai.2001.24551 CrossRefPubMedGoogle Scholar
  38. 38.
    Duman EN, Kesim M, Kadioglu M, Ulku C, Kalyoncu NI, Yaris E (2006) Effect of gender on antinociceptive effect of paroxetine in hot plate test in mice. Prog Neuro-Psychopharmacol Biol Psychiatry 30:292–296.  https://doi.org/10.1016/j.pnpbp.2005.10.012 CrossRefGoogle Scholar
  39. 39.
    Fillingim RB (2002) Sex differences in analgesic responses: evidence from experimental pain models. Eur J Anaesthesiol Suppl 26:16–24 http://www.ncbi.nlm.nih.gov/pubmed/12512212 Accessed 7 Nov 2016CrossRefGoogle Scholar
  40. 40.
    Dudova I, Vodicka J, Havlovicova M, Sedlacek Z, Urbanek T, Hrdlicka M (2011) Odor detection threshold, but not odor identification, is impaired in children with autism. Eur Child Adolesc Psychiatry 20:333–340.  https://doi.org/10.1007/s00787-011-0177-1 CrossRefPubMedGoogle Scholar
  41. 41.
    Leekam SR, Nieto C, Libby SJ, Wing L, Gould J (2007) Describing the sensory abnormalities of children and adults with autism. J Autism Dev Disord 37:894–910.  https://doi.org/10.1007/s10803-006-0218-7 CrossRefPubMedGoogle Scholar
  42. 42.
    Yang M, Crawley JN (2009) Simple behavioral assessment of mouse olfaction. Curr Protoc Neurosci Chapter 8:Unit 8.24.  https://doi.org/10.1002/0471142301.ns0824s48 CrossRefPubMedGoogle Scholar
  43. 43.
    Gallitano-Mendel A, Izumi Y, Tokuda K, Zorumski CF, Howell MP, Muglia LJ et al (2007) The immediate early gene early growth response gene 3 mediates adaptation to stress and novelty. Neuroscience 148:633–643.  https://doi.org/10.1016/j.neuroscience.2007.05.050 CrossRefPubMedGoogle Scholar
  44. 44.
    Bruinsma CF, Schonewille M, Gao Z, Aronica EMA, Judson MC, Philpot BD et al (2015) Dissociation of locomotor and cerebellar deficits in a murine Angelman syndrome model. J Clin Invest 125:4305–4315.  https://doi.org/10.1172/JCI83541 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Heck DH, Zhao Y, Roy S, LeDoux MS, Reiter LT (2008) Analysis of cerebellar function in Ube3a-deficient mice reveals novel genotype-specific behaviors. Hum Mol Genet 17:2181–2189.  https://doi.org/10.1093/hmg/ddn117 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Mulherkar SA, Jana NR (2010) Loss of dopaminergic neurons and resulting behavioural deficits in mouse model of Angelman syndrome. Neurobiol Dis 40:586–592.  https://doi.org/10.1016/j.nbd.2010.08.002 CrossRefPubMedGoogle Scholar
  47. 47.
    Lever C, Burton S, O’Keefe J (2006) Rearing on hind legs, environmental novelty, and the hippocampal formation. Rev Neurosci 17:111–133 http://www.ncbi.nlm.nih.gov/pubmed/16703946 Accessed 30 Nov 2016CrossRefGoogle Scholar
  48. 48.
    Simon P, Dupuis R, Costentin J (1994) Thigmotaxis as an index of anxiety in mice. Influence of dopaminergic transmissions. Behav Brain Res 61:59–64 http://www.ncbi.nlm.nih.gov/pubmed/7913324 Accessed 5 Oct 2016CrossRefGoogle Scholar
  49. 49.
    Wolfer DP, Stagljar-Bozicevic M, Errington ML, Lipp H-P (1998) Spatial memory and learning in transgenic mice: fact or artifact? News Physiol Sci 13:118–123 http://www.ncbi.nlm.nih.gov/pubmed/11390774 Accessed 1 Sep 2016PubMedGoogle Scholar
  50. 50.
    Deacon RMJ (2006) Digging and marble burying in mice: simple methods for in vivo identification of biological impacts. Nat Protoc 1:122–124.  https://doi.org/10.1038/nprot.2006.20 CrossRefPubMedGoogle Scholar
  51. 51.
    Njung’e K, Handley SL (1991) Effects of 5-HT uptake inhibitors, agonists and antagonists on the burying of harmless objects by mice; a putative test for anxiolytic agents. Br J Pharmacol 104:105–112 http://www.ncbi.nlm.nih.gov/pubmed/1686200 Accessed 1 Sep 2016CrossRefGoogle Scholar
  52. 52.
    Londei T, Valentini AM, Leone VG (1998) Investigative burying by laboratory mice may involve non-functional, compulsive, behaviour. Behav Brain Res 94:249–254 http://www.ncbi.nlm.nih.gov/pubmed/9722276 Accessed 1 Sep 2016CrossRefGoogle Scholar
  53. 53.
    Gyertyán I (1995) Analysis of the marble burying response: marbles serve to measure digging rather than evoke burying. Behav Pharmacol 6:24–31 http://www.ncbi.nlm.nih.gov/pubmed/11224308 Accessed 1 Sep 2016CrossRefGoogle Scholar
  54. 54.
    Archer T, Fredriksson A, Lewander T, Söderberg U (1987) Marble burying and spontaneous motor activity in mice: interactions over days and the effect of diazepam. Scand J Psychol 28:242–249 http://www.ncbi.nlm.nih.gov/pubmed/3441771. Accessed 1 Sep 2016CrossRefGoogle Scholar
  55. 55.
    Gray DS, Terlecki LJ, Treit D, Pinel JP (1981) Effect of septal lesions on conditioned defensive burying. Physiol Behav 27:1051–1056 http://www.ncbi.nlm.nih.gov/pubmed/7199741. Accessed 1 Sep 2016CrossRefGoogle Scholar
  56. 56.
    Thomas A, Burant A, Bui N, Graham D, Yuva-Paylor LA, Paylor R (2009) Marble burying reflects a repetitive and perseverative behavior more than novelty-induced anxiety. Psychopharmacology 204:361–373.  https://doi.org/10.1007/s00213-009-1466-y CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Deacon RMJ, Rawlins JNP (2005) Hippocampal lesions, species-typical behaviours and anxiety in mice. Behav Brain Res 156:241–249.  https://doi.org/10.1016/j.bbr.2004.05.027 CrossRefPubMedGoogle Scholar
  58. 58.
    Deacon RMJ (2006) Assessing nest building in mice. Nat Protoc 1:1117–1119.  https://doi.org/10.1038/nprot.2006.170 CrossRefPubMedGoogle Scholar
  59. 59.
    Gaskill BN, Karas AZ, Garner JP, Pritchett-Corning KR. (2013) Nest building as an indicator of health and welfare in laboratory mice. J Vis Exp 82:51012.  https://doi.org/10.3791/51012.
  60. 60.
    van Woerden GM, Harris KD, Hojjati MR, Gustin RM, Qiu S, de Avila Freire R et al (2007) Rescue of neurological deficits in a mouse model for Angelman syndrome by reduction of αCaMKII inhibitory phosphorylation. Nat Neurosci 10:280–282CrossRefGoogle Scholar
  61. 61.
    Dong H-W, Swanson LW, Chen L, Fanselow MS, Toga AW (2009) Genomic-anatomic evidence for distinct functional domains in hippocampal field CA1. Proc Natl Acad Sci U S A 106:11794–11799.  https://doi.org/10.1073/pnas.0812608106 CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Fanselow MS, Dong H-W (2010) Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65:7–19.  https://doi.org/10.1016/j.neuron.2009.11.031 CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Kesner RP, Hunsaker MR, Ziegler W (2011) The role of the dorsal and ventral hippocampus in olfactory working memory. Neurobiol Learn Mem 96:361–366.  https://doi.org/10.1016/j.nlm.2011.06.011 CrossRefPubMedGoogle Scholar
  64. 64.
    Weeden CSS, Hu NJ, Ho LUN, Kesner RP (2014) The role of the ventral dentate gyrus in olfactory pattern separation. Hippocampus 24:553–559.  https://doi.org/10.1002/hipo.22248 CrossRefPubMedGoogle Scholar
  65. 65.
    Trapnell C, Williams BA, Pertea G, Mortazavi A, Kwan G, van Baren MJ et al (2010) Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol 28:511–515.  https://doi.org/10.1038/nbt.1621 CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Carvalho CM, Chang J, Lucas JE, Nevins JR, Wang Q, West M (2008) High-dimensional sparse factor modeling: applications in gene expression genomics. J Am Stat Assoc 103:1438–1456.  https://doi.org/10.1198/016214508000000869 CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Ko Y-A, Saha-Chaudhuri P, Park SK, Vokonas PS, Mukherjee B (2013) Novel likelihood ratio tests for screening gene-gene and gene-environment interactions with unbalanced repeated-measures data. Genet Epidemiol 37:581–591.  https://doi.org/10.1002/gepi.21744 CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM et al (2000) Gene Ontology: tool for the unification of biology. Nat Genet 25:25–29.  https://doi.org/10.1038/75556 CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Davis AP, Grondin CJ, Johnson RJ, Sciaky D, King BL, McMorran R et al (2017) The Comparative Toxicogenomics Database: update 2017. Nucleic Acids Res 45:D972–D978.  https://doi.org/10.1093/nar/gkw838 CrossRefPubMedGoogle Scholar
  70. 70.
    Ultsch A, Kringel D, Kalso E, Mogil JS, Lötsch J (2016) A data science approach to candidate gene selection of pain regarded as a process of learning and neural plasticity. Pain 157:2747–2757.  https://doi.org/10.1097/j.pain.0000000000000694 CrossRefPubMedGoogle Scholar
  71. 71.
    Catoe HW, Nawaz Z (2011) E6-AP facilitates efficient transcription at estrogen responsive promoters through recruitment of chromatin modifiers. Steroids 76:897–902PubMedGoogle Scholar
  72. 72.
    Kühnle S, Mothes B, Matentzoglu K, Scheffner M (2013) Role of the ubiquitin ligase E6AP/UBE3A in controlling levels of the synaptic protein Arc. Proc Natl Acad Sci U S A 110:8888–8893.  https://doi.org/10.1073/pnas.1302792110 CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Khan OY, Fu G, Ismail A, Srinivasan S, Cao X, Tu Y et al (2006) Multifunction steroid receptor coactivator, E6-associated protein, is involved in development of the prostate gland. Mol Endocrinol 20:544–559.  https://doi.org/10.1210/me.2005-0110 CrossRefPubMedGoogle Scholar
  74. 74.
    Bourdeau V, Deschênes J, Métivier R, Nagai Y, Nguyen D, Bretschneider N et al (2004) Genome-wide identification of high-affinity estrogen response elements in human and mouse. Mol Endocrinol 18:1411–1427.  https://doi.org/10.1210/me.2003-0441 CrossRefPubMedGoogle Scholar
  75. 75.
    Bolton EC, So AY, Chaivorapol C, Haqq CM, Li H, Yamamoto KR (2007) Cell- and gene-specific regulation of primary target genes by the androgen receptor. Genes Dev 21:2005–2017.  https://doi.org/10.1101/gad.1564207 CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    McCoy ES, Taylor-Blake B, Aita M, Simon JM, Philpot BD, Zylka MJ (2017) Enhanced nociception in Angelman syndrome Model Mice. J Neurosci 37:10230–10239.  https://doi.org/10.1523/JNEUROSCI.1018-17.2017 CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Cik M, Masure S, Lesage AS, Van Der Linden I, Van Gompel P, Pangalos MN et al (2000) Binding of GDNF and neurturin to human GDNF family receptor alpha 1 and 2. Influence of cRET and cooperative interactions. J Biol Chem 275:27505–27512.  https://doi.org/10.1074/jbc.M000306200 CrossRefPubMedGoogle Scholar
  78. 78.
    Kopra JJ, Panhelainen A, af Bjerkén S, Porokuokka LL, Varendi K, Olfat S et al (2017) Dampened amphetamine-stimulated behavior and altered dopamine transporter function in the absence of brain GDNF. J Neurosci 37:1581–1590.  https://doi.org/10.1523/JNEUROSCI.1673-16.2016 CrossRefPubMedGoogle Scholar
  79. 79.
    Chen K, Li H-Z, Ye N, Zhang J, Wang J-J (2005) Role of GABAB receptors in GABA and baclofen-induced inhibition of adult rat cerebellar interpositus nucleus neurons in vitro. Brain Res Bull 67:310–318.  https://doi.org/10.1016/J.BRAINRESBULL.2005.07.004 CrossRefPubMedGoogle Scholar
  80. 80.
    McCarson KE, Enna SJ (2014) GABA pharmacology: the search for analgesics. Neurochem Res 39:1948–1963.  https://doi.org/10.1007/s11064-014-1254-x CrossRefPubMedGoogle Scholar
  81. 81.
    Clayton JA (2016) Studying both sexes: a guiding principle for biomedicine. FASEB J 30:519–524.  https://doi.org/10.1096/fj.15-279,554 CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Laboratory for Neurobiology of Psychiatric Disorders, Sagol Department of NeurobiologyUniversity of HaifaHaifaIsrael

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