Neurochemical Research

, Volume 44, Issue 6, pp 1494–1507 | Cite as

Atypical Auditory Brainstem Response and Protein Expression Aberrations Related to ASD and Hearing Loss in the Adnp Haploinsufficient Mouse Brain

  • Gal Hacohen-Kleiman
  • Ofer Yizhar-Barnea
  • Olga Touloumi
  • Roza Lagoudaki
  • Karen B. Avraham
  • Nikolaos Grigoriadis
  • Illana GozesEmail author
Original Paper


Autism is a wide spread neurodevelopmental disorder with growing morbidity rates, affecting more boys than girls worldwide. Activity-dependent neuroprotective protein (ADNP) was recently recognized as a leading gene accounted for 0.17% of autism spectrum disorder (ASD) cases globally. Respectively, mutations in the human ADNP gene (ADNP syndrome), cause multi-system body dysfunctions with apparent ASD-related traits, commencing as early as childhood. The Adnp haploinsufficient (Adnp+/−) mouse model was researched before in relations to Alzheimer’s disease and autism. Adnp+/− mice suffer from deficient social memory, vocal and motor impediments, irregular tooth eruption and short stature, all of which corresponds with reported phenotypes in patients with the ADNP syndrome. Recently, a more elaborated description of the ADNP syndrome was published, presenting impediments such as hearing disabilities in > 10% of the studied children. Irregular auditory brainstem response (ABR) has been connected to ASD-related cases and has been suggested as a potential hallmark for autism, allowing diagnosis of ASD risk and early intervention. Herein, we present detriment hearing in the Adnp+/− mice with atypical ABR and significant protein expression irregularities that coincides with ASD and hearing loss studies in the brain.


Activity-dependent neuroprotective protein ADNP ADNP syndrome Hearing loss Developmental delays Auditory brainstem response ABR Adnp haploinsufficient Adnp+/− 



Illana Gozes laboratory is supported by the following grants, Israel Science Foundation (ISF) 1424/14, European Research Area Networks (ERA-NET) neuron AUTISYN, National Science Foundation (NSF) and US-Israel Binational Science Foundation (BSF) 2016746, AMN Foundation as well as Drs. Ronith and Armand Stemmer, Mr Arthur Gerbi (French Friends of Tel Aviv University), and Spanish Friends of Tel Aviv University. This study is in partial fulfillment graduate studies requirements for Gal Hacohen-Kleiman. Gal Hacohen-Kleiman is supported by Eshkol fellowships, the Israel Ministry of Science and Technology. We thank Evangelia Nousiopoulou for the technical support with the immunohistochemistry.

Compliance with Ethical Standards

Conflict of interest

Professor Illana Gozes is the Chief Scientific Officer of Coronis Neurosciences ( developing NAP (CP201) for the ADNP syndrome.

Human and Animal Rights Statement

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the Animal Care and Use Committee of Tel Aviv University and the Israeli Ministry of Health (M-15-059).


  1. 1.
    Autism and Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators (2014) Prevalence of autism spectrum disorder among children aged 8 years—autism and developmental disabilities monitoring network, 11 sites, United States, 2010. MMWR Surveill Summ 63 (2):1–21Google Scholar
  2. 2.
    Campisi L, Imran N, Nazeer A, Skokauskas N, Azeem MW (2018) Autism spectrum disorder. Br Med Bull 127(1):91–100. Google Scholar
  3. 3.
    Gillberg C, Wing L (1999) Autism: not an extremely rare disorder. Acta Psychiatr Scand 99(6):399–406Google Scholar
  4. 4.
    Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, Conroy J, Magalhaes TR,Correia C, Abrahams BS, Almeida J, Bacchelli E, Bader GD, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bolte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Bryson SE, Carson AR, Casallo G, Casey J, Chung BH, Cochrane L, Corsello C, Crawford EL,Crossett A, Cytrynbaum C, Dawson G, de Jonge M, Delorme R, Drmic I, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Freitag CM, Gilbert J,Gillberg C, Glessner JT, Goldberg J, Green A, Green J, Guter SJ, Hakonarson H, Heron EA, Hill M, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Korvatska O, Kustanovich V, Lajonchere CM, Lamb JA, Laskawiec M, Leboyer M, Le Couteur A, Leventhal BL, Lionel AC, Liu XQ, Lord C, Lotspeich L, Lund SC, Maestrini E, Mahoney W, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Merikangas A, Migita O, Minshew NJ, Mirza GK, Munson J, Nelson SF, Noakes C, Noor A, Nygren G, Oliveira G, Papanikolaou K, Parr JR, Parrini B, Paton T, Pickles A, Pilorge M, Piven J, Ponting CP, Posey DJ, Poustka A, Poustka F, Prasad A, Ragoussis J, Renshaw K, Rickaby J, Roberts W, Roeder K, Roge B, Rutter ML, Bierut LJ, Rice JP, Salt J,Sansom K, Sato D, Segurado R, Sequeira AF, Senman L, Shah N, Sheffield VC, Soorya L, Sousa I, Stein O, Sykes N, Stoppioni V, Strawbridge C, Tancredi R, Tansey K, Thiruvahindrapduram B, Thompson AP, Thomson S, Tryfon A, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Wallace S, Wang K, Wang Z, Wassink TH, Webber C, Weksberg R, Wing K, Wittemeyer K, Wood S, Wu J, Yaspan BL, Zurawiecki D, Zwaigenbaum L, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Devlin B, Ennis S, Gallagher L, Geschwind DH, Gill M, Haines JL, Hallmayer J, Miller J, Monaco AP, Nurnberger JI Jr., Paterson AD, Pericak-Vance MA, Schellenberg GD, Szatmari P, Vicente AM, Vieland VJ, Wijsman EM, Scherer SW, Sutcliffe JS, Betancur C (2010) Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466 (7304):368–372. doi:10.1038/nature09146Google Scholar
  5. 5.
    Gillberg C, Billstedt E (2000) Autism and asperger syndrome: coexistence with other clinical disorders. Acta Psychiatr Scand 102(5):321–330Google Scholar
  6. 6.
    Talkowski ME, Rosenfeld JA, Blumenthal I, Pillalamarri V, Chiang C, Heilbut A, Ernst C, Hanscom C, Rossin E, Lindgren AM, Pereira S, Ruderfer D, Kirby A, Ripke S, Harris DJ, Lee JH, Ha K, Kim HG, Solomon BD, Gropman AL, Lucente D, Sims K, Ohsumi TK, Borowsky ML, Loranger S, Quade B, Lage K, Miles J, Wu BL, Shen Y, Neale B, Shaffer LG, Daly MJ, Morton CC, Gusella JF (2012) Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. Cell 149(3):525–537. Google Scholar
  7. 7.
    Panaitof SC (2012) A songbird animal model for dissecting the genetic bases of autism spectrum disorder. Dis Mark 33(5):241–249. Google Scholar
  8. 8.
    Abrahams BS, Geschwind DH (2008) Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet 9(5):341–355. Google Scholar
  9. 9.
    Bassan M, Zamostiano R, Davidson A, Pinhasov A, Giladi E, Perl O, Bassan H, Blat C, Gibney G, Glazner G, Brenneman DE, Gozes I (1999) Complete sequence of a novel protein containing a femtomolar-activity-dependent neuroprotective peptide. J Neurochem 72(3):1283–1293Google Scholar
  10. 10.
    Pinhasov A, Mandel S, Torchinsky A, Giladi E, Pittel Z, Goldsweig AM, Servoss SJ, Brenneman DE, Gozes I (2003) Activity-dependent neuroprotective protein: a novel gene essential for brain formation. Brain Res Dev Brain Res 144(1):83–90Google Scholar
  11. 11.
    Borozdin W, Graham JM Jr, Bohm D, Bamshad MJ, Spranger S, Burke L, Leipoldt M, Kohlhase J (2007) Multigene deletions on chromosome 20q13.13-q13.2 including SALL4 result in an expanded phenotype of Okihiro syndrome plus developmental delay. Hum Mutat 28(8):830Google Scholar
  12. 12.
    Mandel S, Gozes I (2007) Activity-dependent neuroprotective protein constitutes a novel element in the SWI/SNF chromatin remodeling complex. J Biol Chem 282(47):34448–34456Google Scholar
  13. 13.
    Gozes I, Yeheskel A, Pasmanik-Chor M (2014) Activity-dependent neuroprotective protein (ADNP): a case study for highly conserved chordata-specific genes shaping the brain and mutated in cancer. J Alzheimer’s Dis. Google Scholar
  14. 14.
    Helsmoortel C, Vulto-van Silfhout AT, Coe BP, Vandeweyer G, Rooms L, van den Ende J, Schuurs-Hoeijmakers JH, Marcelis CL, Willemsen MH, Vissers LE, Yntema HG, Bakshi M, Wilson M, Witherspoon KT, Malmgren H, Nordgren A, Anneren G, Fichera M, Bosco P, Romano C, de Vries BB, Kleefstra T, Kooy RF, Eichler EE, Van der Aa N (2014) A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP. Nat Genet 46(4):380–384. Google Scholar
  15. 15.
    Gozes I, Helsmoortel C, Vandeweyer G, Van der Aa N, Kooy F, Sermone SB (2015) The compassionate side of neuroscience: Tony Sermone’s undiagnosed genetic journey–ADNP mutation. J Mol Neurosci 56(4):751–757. Google Scholar
  16. 16.
    Gozes I, Patterson MC, Van Dijck A, Kooy RF, Peeden JN, Eichenberger JA, Zawacki-Downing A, Bedrosian-Sermone S (2017) The eight and a half year journey of undiagnosed AD: gene sequencing and funding of advanced genetic testing has led to hope and new beginnings. Front Endocrinol 8:107. Google Scholar
  17. 17.
    Malishkevich A, Amram N, Hacohen-Kleiman G, Magen I, Giladi E, Gozes I (2015) Activity-dependent neuroprotective protein (ADNP) exhibits striking sexual dichotomy impacting on autistic and Alzheimer’s pathologies. Transl Psychiatr 5:e501. Google Scholar
  18. 18.
    Amram N, Hacohen-Kleiman G, Sragovich S, Malishkevich A, Katz J, Touloumi O, Lagoudaki R, Grigoriadis NC, Giladi E, Yeheskel A, Pasmanik-Chor M, Jouroukhin Y, Gozes I (2016) Sexual divergence in microtubule function: the novel intranasal microtubule targeting SKIP normalizes axonal transport and enhances memory. Mol Psychiatr. Google Scholar
  19. 19.
    Hacohen-Kleiman G, Sragovich S, Karmon G, Gao AYL, Grigg I, Pasmanik-Chor M, Le A, Korenkova V, McKinney RA, Gozes I (2018) Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome. J Clin Investig 128(11):4956–4969. Google Scholar
  20. 20.
    Gkogkas CG, Khoutorsky A, Ran I, Rampakakis E, Nevarko T, Weatherill DB, Vasuta C, Yee S, Truitt M, Dallaire P, Major F, Lasko P, Ruggero D, Nader K, Lacaille JC, Sonenberg N (2013) Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature 493(7432):371–377. Google Scholar
  21. 21.
    Van Dijck A, Vulto-van Silfhout AT, Cappuyns E, van der Werf IM, Mancini GM, Tzschach A, Bernier R, Gozes I, Eichler EE, Romano C, Lindstrand A, Nordgren A, Consortium A, Kvarnung M, Kleefstra T, de Vries BBA, Kury S, Rosenfeld JA, Meuwissen ME, Vandeweyer G, Kooy RF (2018) Clinical presentation of a complex neurodevelopmental disorder caused by mutations in ADNP. Biol Psychiatr. Google Scholar
  22. 22.
    Miron O, Roth DAE, Gabis LV, Henkin Y, Shefer S, Dinstein I, Geva R (2016) Prolonged auditory brainstem responses in infants with autism. Autism Res 9(6):689–695. Google Scholar
  23. 23.
    World-Health-Organization (2010) Newborn and infant hearing screening—current issues and guiding principels for action outcome of a WHO informal consultation. WHO, GenevaGoogle Scholar
  24. 24.
    Fujikawa-Brooks S, Isenberg AL, Osann K, Spence MA, Gage NM (2010) The effect of rate stress on the auditory brainstem response in autism: a preliminary report. Int J Audiol 49(2):129–140. Google Scholar
  25. 25.
    Kwon S, Kim J, Choe BH, Ko C, Park S (2007) Electrophysiologic assessment of central auditory processing by auditory brainstem responses in children with autism spectrum disorders. J Korean Med Sci 22(4):656–659. Google Scholar
  26. 26.
    Roth DA, Muchnik C, Shabtai E, Hildesheimer M, Henkin Y (2012) Evidence for atypical auditory brainstem responses in young children with suspected autism spectrum disorders. Dev Med Child Neurol 54(1):23–29. Google Scholar
  27. 27.
    Miron O, Beam AL, Kohane IS (2018) Auditory brainstem response in infants and children with autism spectrum disorder: a meta-analysis of wave V. Autism Res 11(2):355–363. Google Scholar
  28. 28.
    Vulih-Shultzman I, Pinhasov A, Mandel S, Grigoriadis N, Touloumi O, Pittel Z, Gozes I (2007) Activity-dependent neuroprotective protein snippet NAP reduces tau hyperphosphorylation and enhances learning in a novel transgenic mouse model. J Pharmacol Exp Ther 323(2):438–449Google Scholar
  29. 29.
    Walsh VL, Raviv D, Dror AA, Shahin H, Walsh T, Kanaan MN, Avraham KB, King MC (2011) A mouse model for human hearing loss DFNB30 due to loss of function of myosin IIIA. Mamm Genome 22(3–4):170–177. Google Scholar
  30. 30.
    Muller U, Barr-Gillespie PG (2015) New treatment options for hearing loss. Nat Rev Drug Discov 14(5):346–384. Google Scholar
  31. 31.
    McCullough BJ, BL T (2004) Haplo-insufficiency revealed in deafwaddler mice when tested for hearing loss and ataxia. Hear Res 195(1–2):90–102. Google Scholar
  32. 32.
    Shu W, Cho JY, Jiang Y, Zhang M, Weisz D, Elder GA, Schmeidler J, De Gasperi R, Sosa MA, Rabidou D, Santucci AC, Perl D, Morrisey E, Buxbaum JD (2005) Altered ultrasonic vocalization in mice with a disruption in the Foxp2 gene. Proc Natl Acad Sci USA 102(27):9643–9648. Google Scholar
  33. 33.
    Hertzano R, Montcouquiol M, Rashi-Elkeles S, Elkon R, Yucel R, Frankel WN, Rechavi G, Moroy T, Friedman TB, Kelley MW, Avraham KB (2004) Transcription profiling of inner ears from Pou4f3(ddl/ddl) identifies Gfi1 as a target of the Pou4f3 deafness gene. Hum Mol Genet 13(18):2143–2153. Google Scholar
  34. 34.
    Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, Santos A, Doncheva NT, Roth A, Bork P, Jensen LJ, von Mering C (2017) The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res 45(D1):D362–D368. Google Scholar
  35. 35.
    Zhou X, Jen PH, Seburn KL, Frankel WN, Zheng QY (2006) Auditory brainstem responses in 10 inbred strains of mice. Brain Res 1091(1):16–26. Google Scholar
  36. 36.
    Burkard RF, Eggermont JJ, Manuel D (eds) (2007) Auditory evoked potentials: basic principles and clinical application. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  37. 37.
    Hodges SL, Nolan SO, Reynolds CD, Lugo JN (2017) Spectral and temporal properties of calls reveal deficits in ultrasonic vocalizations of adult Fmr1 knockout mice. Behav Brain Res 332:50–58. Google Scholar
  38. 38.
    Oz S, Kapitansky O, Ivashco-Pachima Y, Malishkevich A, Giladi E, Skalka N, Rosin-Arbesfeld R, Mittelman L, Segev O, Hirsch JA, Gozes I (2014) The NAP motif of activity-dependent neuroprotective protein (ADNP) regulates dendritic spines through microtubule end binding proteins. Mol Psychiatr 19(10):1115–1124. Google Scholar
  39. 39.
    Ivashko-Pachima Y, Sayas CL, Malishkevich A, Gozes I (2017) ADNP/NAP dramatically increase microtubule end-binding protein-Tau interaction: a novel avenue for protection against tauopathy. Mol Psychiatr 22(9):1335–1344. Google Scholar
  40. 40.
    Dong S, Mulders WHAM, Rodger J, Robertson D (2009) Changes in neuronal activity and gene expression in guinea-pig auditory brainstem after unilateral partial hearing loss. Neuroscience 159(3):1164–1174. Google Scholar
  41. 41.
    Sarro EC, Kotak VC, Sanes DH, Aoki C (2008) Hearing loss alters the subcellular distribution of presynaptic GAD and postsynaptic GABAA receptors in the auditory cortex. Cerebral Cortex 18(12):2855–2867. Google Scholar
  42. 42.
    Godfrey DA, Kaltenbach JA, Chen K, Ilyas O (2013) Choline acetyltransferase activity in the hamster central auditory system and long-term effects of intense tone exposure. J Neurosci Res 91(7):987–996. Google Scholar
  43. 43.
    Bauer CA, Kurt W, Sybert LT, Brozoski TJ (2013) The cerebellum as a novel tinnitus generator. Hear Res 295:130–139Google Scholar
  44. 44.
    Wang SS, Kloth AD, Badura A (2014) The cerebellum, sensitive periods, and autism. Neuron 83(3):518–532. Google Scholar
  45. 45.
    Miron O, Ari-Even Roth D, Gabis LV, Henkin Y, Shefer S, Dinstein I, Geva R (2016) Prolonged auditory brainstem responses in infants with autism. Autism Res 9(6):689–695. Google Scholar
  46. 46.
    Gozes I, Van Dijck A, Hacohen-Kleiman G, Grigg I, Karmon G, Giladi E, Eger M, Gabet Y, Pasmanik-Chor M, Cappuyns E, Elpeleg O, Kooy RF, Bedrosian-Sermone S (2017) Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children. Transl Psychiatr 7(2):e1043. Google Scholar
  47. 47.
    Shulz DE, Cohen S, Haidarliu S, Ahissar E (1997) Differential effects of acetylcholine on neuronal activity and interactions in the auditory cortex of the guinea-pig. Eur J Neurosci 9(2):396–409Google Scholar
  48. 48.
    Chavez C, Zaborszky L (2017) Basal forebrain cholinergic-auditory cortical network: primary versus nonprimary auditory cortical areas. Cerebral cortex 27(3):2335–2347. Google Scholar
  49. 49.
    Chauhan PS, Misra UK, Kalita J, Chandravanshi LP, Khanna VK (2016) Memory and learning seems to be related to cholinergic dysfunction in the JE rat model. Physiol Behav 156:148–155. Google Scholar
  50. 50.
    Nordberg A, Alafuzoff I, Winblad B (1986) Muscarinic receptor subtypes in hippocampus in Alzheimer’s disease and mixed dementia type. Neurosci Lett 70(1):160–164Google Scholar
  51. 51.
    Vreugdenhil M, Jefferys JG, Celio MR, Schwaller B (2003) Parvalbumin-deficiency facilitates repetitive IPSCs and gamma oscillations in the hippocampus. J Neurophysiol 89(3):1414–1422. Google Scholar
  52. 52.
    Wohr M, Orduz D, Gregory P, Moreno H, Khan U, Vorckel KJ, Wolfer DP, Welzl H, Gall D, Schiffmann SN, Schwaller B (2015) Lack of parvalbumin in mice leads to behavioral deficits relevant to all human autism core symptoms and related neural morphofunctional abnormalities. Transl Psychiatr 5:e525. Google Scholar
  53. 53.
    Martin del Campo HN, Measor KR, Razak KA (2012) Parvalbumin immunoreactivity in the auditory cortex of a mouse model of presbycusis. Hear Res 294(1–2):31–39. Google Scholar
  54. 54.
    Penttonen M, Kamondi A, Acsady L, Buzsaki G (1998) Gamma frequency oscillation in the hippocampus of the rat: intracellular analysis in vivo. Eur J Neurosci 10(2):718–728Google Scholar
  55. 55.
    Nguyen MV, Du F, Felice CA, Shan X, Nigam A, Mandel G, Robinson JK, Ballas N (2012) MeCP2 is critical for maintaining mature neuronal networks and global brain anatomy during late stages of postnatal brain development and in the mature adult brain. J Neurosci 32(29):10021–10034. Google Scholar
  56. 56.
    Zhang FX, Ge SN, Dong YL, Shi J, Feng YP, Li Y, Li YQ, Li JL (2018) Vesicular glutamate transporter isoforms: the essential players in the somatosensory systems. Progr Neurobiol. Google Scholar
  57. 57.
    Caporali P, Bruno F, Palladino G, Dragotto J, Petrosini L, Mangia F, Erickson RP, Canterini S, Fiorenza MT (2016) Developmental delay in motor skill acquisition in Niemann-Pick C1 mice reveals abnormal cerebellar morphogenesis. Acta Neuropathol Commun 4(1):94. Google Scholar
  58. 58.
    Nualart-Marti A, Solsona C, Fields RD (2013) Gap junction communication in myelinating glia. Biochim Biophys acta 1828(1):69–78. Google Scholar
  59. 59.
    Yamasaki R (2018) Connexins in health and disease. Clin Exp Neuroimmunol 9:30–36Google Scholar
  60. 60.
    Maezawa I, Calafiore M, Wulff H, Jin LW (2011) Does microglial dysfunction play a role in autism and Rett syndrome? Neuron glia Biol 7(1):85–97. Google Scholar
  61. 61.
    Abbasian M, Sayyah M, Babapour V, Mahdian R (2013) Intracerebroventricular injection of lipopolysaccharide increases gene expression of connexin32 gap junction in rat hippocampus. Basic Clin Neurosci 4(4):334–340Google Scholar
  62. 62.
    Braitch M, Kawabe K, Nyirenda M, Gilles LJ, Robins RA, Gran B, Murphy S, Showe L, Constantinescu CS (2010) Expression of activity-dependent neuroprotective protein in the immune system: possible functions and relevance to multiple sclerosis. Neuroimmunomodulation 17(2):120–125. Google Scholar
  63. 63.
    Wasseff SK, Scherer SS (2015) Activated immune response in an inherited leukodystrophy disease caused by the loss of oligodendrocyte gap junctions. Neurobiol Dis 82:86–98. Google Scholar
  64. 64.
    Maturana CJ, Aguirre A, Saez JC (2017) High glucocorticoid levels during gestation activate the inflammasome in hippocampal oligodendrocytes of the offspring. Dev Neurobiol 77(5):625–642. Google Scholar
  65. 65.
    Hou Q, Wang Y, Li Y, Chen D, Yang F, Wang S (2018) A developmental study of abnormal behaviors and altered GABAergic signaling in the VPA-treated rat model of autism. Front Behav Neurosci 12:182. Google Scholar
  66. 66.
    Teramitsu I, Kudo LC, London SE, Geschwind DH, White SA (2004) Parallel FoxP1 and FoxP2 expression in songbird and human brain predicts functional interaction. J Neurosci 24(13):3152–3163. Google Scholar
  67. 67.
    Haesler S, Rochefort C, Georgi B, Licznerski P, Osten P, Scharff C (2007) Incomplete and inaccurate vocal imitation after knockdown of FoxP2 in songbird basal ganglia nucleus Area X. PLoS Biol 5(12):e321. Google Scholar
  68. 68.
    Lai CS, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP (2001) A forkhead-domain gene is mutated in a severe speech and language disorder. Nature 413(6855):519–523. Google Scholar
  69. 69.
    Bowers JM, Konopka G (2012) ASD-relevant animal models of the Foxp family of transcription factors. Autism-Open Access Suppl. Google Scholar
  70. 70.
    Coutinho P, Pavlou S, Bhatia S, Chalmers KJ, Kleinjan DA, van Heyningen V (2011) Discovery and assessment of conserved Pax6 target genes and enhancers. Genome Res 21(8):1349–1359. Google Scholar
  71. 71.
    Vaisburd S, Shemer Z, Yeheskel A, Giladi E, Gozes I (2015) Risperidone and NAP protect cognition and normalize gene expression in a schizophrenia mouse model. Sci Rep 5:16300. Google Scholar
  72. 72.
    Sia GM, Clem RL, Huganir RL (2013) The human language-associated gene SRPX2 regulates synapse formation and vocalization in mice. Science 342(6161):987–991. Google Scholar
  73. 73.
    Sutor B, Hagerty T (2005) Involvement of gap junctions in the development of the neocortex. Biochim biophys acta 1719(1–2):59–68. Google Scholar
  74. 74.
    Caillard O, Moreno H, Schwaller B, Llano I, Celio MR, Marty A (2000) Role of the calcium-binding protein parvalbumin in short-term synaptic plasticity. Proc Natl Acad Sci USA 97(24):13372–13377. Google Scholar
  75. 75.
    Becker EB, Stoodley CJ (2013) Autism spectrum disorder and the cerebellum. Int Rev Neurobiol 113:1–34. Google Scholar
  76. 76.
    Parikshak NN, Luo R, Zhang A, Won H, Lowe JK, Chandran V, Horvath S, Geschwind DH (2013) Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell 155(5):1008–1021. Google Scholar
  77. 77.
    Rotstein M, Bassan H, Kariv N, Speiser Z, Harel S, Gozes I (2006) NAP enhances neurodevelopment of newborn apolipoprotein E-deficient mice subjected to hypoxia. J Pharmacol Exp Ther 319(1):332–339. Google Scholar
  78. 78.
    Fiez JA, Raichle ME, Balota DA, Tallal P, Petersen SE (1996) PET activation of posterior temporal regions during auditory word presentation and verb generation. Cerebral Cortex 6(1):1–10Google Scholar
  79. 79.
    Schlosser R, Hutchinson M, Joseffer S, Rusinek H, Saarimaki A, Stevenson J, Dewey SL, Brodie JD (1998) Functional magnetic resonance imaging of human brain activity in a verbal fluency task. J Neurol Neurosurg Psychiatr 64(4):492–498Google Scholar
  80. 80.
    Petacchi A, Laird AR, Fox PT, Bower JM (2005) Cerebellum and auditory function: an ALE meta-analysis of functional neuroimaging studies. Hum Brain Mapp 25(1):118–128. Google Scholar
  81. 81.
    Yang G, Lobarinas E, Zhang L, Turner J, Stolzberg D, Salvi R, Sun W (2007) Salicylate induced tinnitus: behavioral measures and neural activity in auditory cortex of awake rats. Hear Res 226(1–2):244–253. Google Scholar
  82. 82.
    Yang S, Weiner BD, Zhang LS, Cho SJ, Bao S (2011) Homeostatic plasticity drives tinnitus perception in an animal model. Proc Natl Acad Sci USA 108(36):14974–14979. Google Scholar
  83. 83.
    Shulman A, Strashun A (1999) Descending auditory system/cerebellum/tinnitus. Int Tinnitus J 5(2):92–106Google Scholar
  84. 84.
    Mirz F, Pedersen B, Ishizu K, Johannsen P, Ovesen T, Stodkilde-Jorgensen H, Gjedde A (1999) Positron emission tomography of cortical centers of tinnitus. Hear Res 134(1–2):133–144Google Scholar
  85. 85.
    Azizi SA, Burne RA, Woodward DJ (1985) The auditory corticopontocerebellar projection in the rat: inputs to the paraflocculus and midvermis. An anatomical and physiological study. Exp Brain Res 59(1):36–49Google Scholar
  86. 86.
    Chang A, Chen P, Guo S, Xu N, Pan W, Zhang H, Li C, Tang J (2018) Specific influences of early acoustic environments on cochlear hair cells in postnatal mice. Neural Plast 2018:5616930. Google Scholar

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Authors and Affiliations

  1. 1.The Lily and Avrahamo Gildor Chair for the Investigation of Growth Factors; The Elton Laboratory for Neuroendocrinology; Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Sagol School of Neuroscience and Adams Super Center for Brain StudiesTel Aviv UniversityTel AvivIsrael
  2. 2.Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of NeuroscienceTel Aviv UniversityTel AvivIsrael
  3. 3.Department of Neurology, Laboratory of Experimental NeurologyAHEPA University Hospital, Aristotle University of ThessalonikiThessalonikiGreece

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