Top

Journal of Neurodevelopmental Disorders

Published in:

Open Access 01-12-2015 | Research

Complete or partial reduction of the Met receptor tyrosine kinase in distinct circuits differentially impacts mouse behavior

Authors: Barbara L. Thompson, Pat Levitt

Published in: Journal of Neurodevelopmental Disorders | Issue 1/2015

Abstract

Background

Our laboratory discovered that the gene encoding the receptor tyrosine kinase, MET, contributes to autism risk. Expression of MET is reduced in human postmortem temporal lobe in autism and Rett Syndrome. Subsequent studies revealed a role for MET in human and mouse functional and structural cortical connectivity. To further understand the contribution of Met to brain development and its impact on behavior, we generated two conditional mouse lines in which Met is deleted from select populations of central nervous system neurons. Mice were then tested to determine the consequences of disrupting Met expression.

Methods

Mating of Emx1 ^cre and Met ^fx/fx mice eliminates receptor signaling from all cells arising from the dorsal pallium. Met ^fx/fx and Nestin ^cre crosses result in receptor signaling elimination from all neural cells. Behavioral tests were performed to assess cognitive, emotional, and social impairments that are observed in multiple neurodevelopmental disorders and that are in part subserved by circuits that express Met.

Results

Met ^fx/fx/Emx1 ^cre null mice displayed significant hypoactivity in the activity chamber and in the T-maze despite superior performance on the rotarod. Additionally, these animals showed a deficit in spontaneous alternation. Surprisingly, Met ^{fx/fx; fx/+}/Nestin ^cre null and heterozygous mice exhibited deficits in contextual fear conditioning, and Met ^fx/+/Nestin ^cre heterozygous mice spent less time in the closed arms of the elevated plus maze.

Conclusions

These data suggest a complex contribution of Met in the development of circuits mediating social, emotional, and cognitive behavior. The impact of disrupting developmental Met expression is dependent upon circuit-specific deletion patterns and levels of receptor activity.

Available only for authorised users

Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF, et al. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science. 1991;251(4995):802–4.PubMedCrossRef

Graveel CR, Tolbert D, Vande Woude GF. MET: a critical player in tumorigenesis and therapeutic target. Cold Spring Harb Perspect Biol. 2013;5(7):a009209.PubMedCentralPubMedCrossRef

Judson MC, Eagleson KL, Wang L, Levitt P. Evidence of cell-nonautonomous changes in dendrite and dendritic spine morphology in the met-signaling-deficient mouse forebrain. J Comp Neurol. 2010;518(21):4463–78. doi:10.1002/cne.22467.PubMedCentralPubMedCrossRef

Lim CS, Walikonis RS. Hepatocyte growth factor and c-Met promote dendritic maturation during hippocampal neuron differentiation via the Akt pathway. Cell Signal. 2008;20(5):825–35. doi:10.1016/j.cellsig.2007.12.013.PubMedCentralPubMedCrossRef

Tyndall SJ, Patel SJ, Walikonis RS. Hepatocyte growth factor-induced enhancement of dendritic branching is blocked by inhibitors of N-methyl-D-aspartate receptors and calcium/calmodulin-dependent kinases. J Neurosci Res. 2007;85(11):2343–51.PubMedCrossRef

Qiu S, Aldinger KA, Levitt P. Modeling of autism genetic variations in mice: focusing on synaptic and microcircuit dysfunctions. Dev Neurosci. 2012;34(2-3):88–100.PubMedCrossRef

Peng Y, Huentelman M, Smith C, Qiu S. MET receptor tyrosine kinase as an autism genetic risk factor, Bioinformatics of behavior: part 2. 1st ed. Philadelphia: Elsevier Inc; 2014. p. 135–65.

Qiu S, Lu Z, Levitt P. MET receptor tyrosine kinase controls dendritic complexity, spine morphogenesis, and glutamatergic synapse maturation in the hippocampus. J Neurosci. 2014;34(49):16166–79.PubMedCentralPubMedCrossRef

Eagleson KL, Milner TA, Xie Z, Levitt P. Synaptic and extrasynaptic location of the receptor tyrosine kinase met during postnatal development in the mouse neocortex and hippocampus. J Comp Neurol. 2013;521(14):3241–59. doi:10.1002/cne.23343.PubMedCentralPubMedCrossRef

10.

Judson MC, Amaral DG, Levitt P. Conserved subcortical and divergent cortical expression of proteins encoded by orthologs of the autism risk gene MET. Cereb Cortex. 2011;21(7):1613–26. doi:10.1093/cercor/bhq223.PubMedCentralPubMedCrossRef

11.

Judson MC, Bergman MY, Campbell DB, Eagleson KL, Levitt P. Dynamic gene and protein expression patterns of the autism-associated met receptor tyrosine kinase in the developing mouse forebrain. J Comp Neurol. 2009;513(5):511–31. doi:10.1002/cne.21969.PubMedCentralPubMedCrossRef

12.

Eagleson KL, Campbell DB, Thompson BL, Bergman MY, Levitt P. The autism risk genes MET and PLAUR differentially impact cortical development. Autism Res. 2010;4(1):68–83.PubMedCentralPubMedCrossRef

13.

Mukamel Z, Konopka G, Wexler E, Osborn GE, Dong H, Bergman MY, et al. Regulation of MET by FOXP2, genes implicated in higher cognitive dysfunction and autism risk. J Neurosci. 2011;31(32):11437–42. doi:10.1523/JNEUROSCI.0181-11.2011.PubMedCentralPubMedCrossRef

14.

Bernard A, Lubbers LS, Tanis KQ, Luo R, Podtelezhnikov AA, Finney EM, et al. Transcriptional architecture of the primate neocortex. Neuron. 2012;73(6):1083–99.PubMedCentralPubMedCrossRef

15.

Qiu S, Anderson CT, Levitt P, Shepherd GM. Circuit-specific intracortical hyperconnectivity in mice with deletion of the autism-associated Met receptor tyrosine kinase. J Neurosci. 2011;31(15):5855–64. doi:10.1523/JNEUROSCI.6569-10.2011.PubMedCentralPubMedCrossRef

16.

Campbell DB, Li C, Sutcliffe JS, Persico AM, Levitt P. Genetic evidence implicating multiple genes in the MET receptor tyrosine kinase pathway in autism spectrum disorder. Autism Res. 2008;1(3):159–68.PubMedCentralPubMedCrossRef

17.

Jackson PB, Boccuto L, Skinner C, Collins JS, Neri G, Gurrieri F, et al. Further evidence that the rs1858830 C variant in the promoter region of the MET gene is associated with autistic disorder. Autism Res. 2009;2(4):232–6.PubMedCrossRef

18.

Thanseem I, Nakamura K, Miyachi T, Toyota T, Yamada S, Tsujii M, et al. Further evidence for the role of MET in autism susceptibility. Neurosci Res. 2010;68(2):137–41.PubMedCrossRef

19.

Abrahams BS, Arking DE, Campbell DB, Mefford HC, Morrow EM, Weiss LA, et al. SFARI Gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs). Molecular Autism. 2013;4(1):1.CrossRef

20.

Campbell DB, D’Oronzio R, Garbett K, Ebert PJ, Mirnics K, Levitt P, et al. Disruption of cerebral cortex MET signaling in autism spectrum disorder. Ann Neurol. 2007;62(3):243–50. doi:10.1002/ana.21180.PubMedCrossRef

21.

Campbell DB, Sutcliffe JS, Ebert PJ, Militerni R, Bravaccio C, Trillo S, et al. A genetic variant that disrupts MET transcription is associated with autism. Proc Natl Acad Sci U S A. 2006;103(45):16834–9. doi:10.1073/pnas.0605296103.PubMedCentralPubMedCrossRef

22.

Heuer L, Braunschweig D, Ashwood P, Van de Water J, Campbell DB. Association of a MET genetic variant with autism-associated maternal autoantibodies to fetal brain proteins and cytokine expression. Translational Psychiatry. 2011;1(10):e48–7.PubMedCentralPubMedCrossRef

23.

Lambert N, Wermenbol V, Pichon B, Acosta S, van den Ameele J, Perazzolo C, et al. A familial heterozygous null mutation of MET in autism spectrum disorder. Autism Res. 2014;7(5):617–22.PubMedCrossRef

24.

Campbell DB, Warren D, Sutcliffe JS, Lee EB, Levitt P. Association of MET with social and communication phenotypes in individuals with autism spectrum disorder. Am J Med Genet. 2009. doi:10.1002/ajmg.b.30998.

25.

Rudie JD, Hernandez LM, Brown JA, Beck-Pancer D, Colich NL, Gorrindo P, et al. Autism-associated promoter variant in MET impacts functional and structural brain networks. Neuron. 2012;75(5):904–15. doi:10.1016/j.neuron.2012.07.010.PubMedCentralPubMedCrossRef

26.

Hedrick A, Lee Y, Wallace GL, Greenstein D, Clasen L, Giedd JN, et al. Autism risk gene MET variation and cortical thickness in typically developing children and adolescents. Autism Res. 2012;5(6):434–9. doi:10.1002/aur.1256.PubMedCentralPubMedCrossRef

27.

Ey E, Leblond CS, Bourgeron T. Behavioral profiles of mouse models for autism spectrum disorders. Autism Res. 2011;4(1):5–16.PubMedCrossRef

28.

Crawley JN. Behavioral phenotyping strategies for mutant mice. Neuron. 2008;57(6):809–18.PubMedCrossRef

29.

Hamilton SM, Spencer CM, Harrison WR, Yuva-Paylor LA, Graham DF, Daza RAM, et al. Multiple autism-like behaviors in a novel transgenic mouse model. Behav Brain Res. 2011;218(1):29–41.PubMedCentralPubMedCrossRef

30.

Ebens A, Brose K, Leonardo ED, Hanson MG, Bladt F, Birchmeier C, et al. Hepatocyte growth factor/scatter factor is an axonal chemoattractant and a neurotrophic factor for spinal motor neurons. Neuron. 1996;17(6):1157–72.PubMedCrossRef

31.

Gorski JA, Talley T, Qiu M, Puelles L, Rubenstein JL, Jones KR. Cortical excitatory neurons and glia, but not GABAergic neurons, are produced in the Emx1-expressing lineage. J Neurosci. 2002;22(15):6309–14.PubMed

32.

Krysko O, Hulshagen L, Janssen A, Schütz G, Klein R, De Bruycker M, et al. Neocortical and cerebellar developmental abnormalities in conditions of selective elimination of peroxisomes from brain or from liver. J Neurosci Res. 2007;85(1):58–72.PubMedCrossRef

33.

Huh CG, Factor VM, Sanchez A, Uchida K, Conner EA, Thorgeirsson SS. Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc Natl Acad Sci U S A. 2004;101(13):4477–82.PubMedCentralPubMedCrossRef

34.

Crawley JN. Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests. Brain Res. 1999;835(1):18–26.PubMedCrossRef

35.

Tapp JT, Wehby JH, Ellis D. MOOSES: a multi-option observation system for experimental studies. Behav Res Methods, Instruments, Computers. 1995;27:25–31.CrossRef

36.

Thomas A, Burant A, Bui N, Graham D, Yuva-Paylor LA, Paylor R. Marble burying reflects a repetitive and perseverative behavior more than novelty-induced anxiety. Psychopharmacology (Berl). 2009;204(2):361–73. doi:10.1007/s00213-009-1466-y.CrossRef

37.

Hughes RN. The value of spontaneous alternation behavior (SAB) as a test of retention in pharmacological investigations of memory. Neurosci Biobehav Rev. 2004;28(5):497–505. doi:10.1016/j.neubiorev.2004.06.006.PubMedCrossRef

38.

Lalonde R. The neurobiological basis of spontaneous alternation. Neurosci Biobehav Rev. 2002;26(1):91–104.PubMedCrossRef

39.

Katz RJ, Chudler R. Y-maze behavior after an analog of ACTH 4–9, evidence for an attentional alteration. Psychopharmacology. 1980;71(1):95–6.PubMedCrossRef

40.

Kokkinidis L, Anisman H. Interaction between cholinergic and catecholaminergic agents in a spontaneous alternation task. Psychopharmacology. 1976;48(3):261–70.PubMedCrossRef

41.

Ueno K, Togashi H, Matsumoto M, Ohashi S, Saito H, Yoshioka M. Alpha4beta2 nicotinic acetylcholine receptor activation ameliorates impairment of spontaneous alternation behavior in stroke-prone spontaneously hypertensive rats, an animal model of attention deficit hyperactivity disorder. J Pharmacol Exp Ther. 2002;302(1):95–100.PubMedCrossRef

42.

Ueno KI, Togashi H, Mori K, Matsumoto M, Ohashi S, Hoshino A, et al. Behavioural and pharmacological relevance of stroke-prone spontaneously hypertensive rats as an animal model of a developmental disorder. Behav Pharmacol. 2002;13(1):1–13.PubMedCrossRef

43.

Wall PM, Blanchard RJ, Markham C, Yang M, Blanchard DC. Infralimbic D1 receptor agonist effects on spontaneous novelty exploration and anxiety-like defensive responding in CD-1 mice. Behav Brain Res. 2004;152(1):67–79. doi:10.1016/j.bbr.2003.09.035.PubMed

44.

Wall PM, Blanchard RJ, Yang M, Blanchard DC. Infralimbic D2 receptor influences on anxiety-like behavior and active memory/attention in CD-1 mice. Prog Neuro-Psychopharmacol Biol Psychiatry. 2003;27(3):395–410. doi:10.1016/S0278-5846(02)00356-1.CrossRef

45.

Thompson BL, Levitt P, Stanwood GD. Prenatal cocaine exposure specifically alters spontaneous alternation behavior. Behav Brain Res. 2005;164(1):107–16.PubMedCrossRef

46.

Bielsky IF, Hu SB, Ren X, Terwilliger EF, Young LJ. The V1a vasopressin receptor is necessary and sufficient for normal social recognition: a gene replacement study. Neuron. 2005;47(4):503–13. doi:10.1016/j.neuron.2005.06.031.PubMedCrossRef

47.

Ferguson JN, Young LJ, Hearn EF, Matzuk MM, Insel TR, Winslow JT. Social amnesia in mice lacking the oxytocin gene. Nat Genet. 2000;25(3):284–8. doi:10.1038/77040.PubMedCrossRef

48.

Ferkin MH, Li HZ. A battery of olfactory-based screens for phenotyping the social and sexual behaviors of mice. Physiol Behav. 2005;85(4):489–99. doi:10.1016/j.physbeh.2005.05.014.PubMedCrossRef

49.

Moy SS, Nadler JJ, PEREZ A, Barbaro RP, Johns JM, Magnuson TR, et al. Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behavior in mice. Genes Brain Behav. 2004;3(5):287–302.PubMedCrossRef

50.

Gutierrez H, Dolcet X, Tolcos M, Davies A. HGF regulates the development of cortical pyramidal dendrites. Development. 2004;131(15):3717–26.PubMedCrossRef

51.

Maski KP, Jeste SS, Spence SJ. Common neurological co-morbidities in autism spectrum disorders. Curr Opin Pediatr. 2011;23(6):609–15. doi:10.1097/MOP.0b013e32834c9282.PubMedCentralPubMedCrossRef

52.

Bauman ML. Medical comorbidities in autism: challenges to diagnosis and treatment. Neurotherapeutics : J American Soc Experimental NeuroTherapeutics. 2010;7(3):320–7. doi:10.1016/j.nurt.2010.06.001.CrossRef

53.

Croen LA, Zerbo O, Qian Y, Massolo ML, Rich S, Sidney S, et al. The health status of adults on the autism spectrum. Autism : Int Journal Res Pract. 2015. doi:10.1177/1362361315577517.

54.

Wohr M, Silverman JL, Scattoni ML, Turner SM, Harris MJ, Saxena R, et al. Developmental delays and reduced pup ultrasonic vocalizations but normal sociability in mice lacking the postsynaptic cell adhesion protein neuroligin2. Behav Brain Res. 2013;251:50–64. doi:10.1016/j.bbr.2012.07.024.PubMedCentralPubMedCrossRef

55.

Pagani JH, Williams Avram SK, Cui Z, Song J, Mezey E, Senerth JM, et al. Raphe serotonin neuron-specific oxytocin receptor knockout reduces aggression without affecting anxiety-like behavior in male mice only. Genes Brain Behav. 2015;14(2):167–76. doi:10.1111/gbb.12202.PubMedCrossRef

56.

Mosienko V, Beis D, Alenina N, Wohr M. Reduced isolation-induced pup ultrasonic communication in mouse pups lacking brain serotonin. Molecular Autism. 2015;6:13. doi:10.1186/s13229-015-0003-6.PubMedCentralPubMedCrossRef

57.

Joeyen-Waldorf J, Edgar N, Sibille E. The roles of sex and serotonin transporter levels in age- and stress-related emotionality in mice. Brain Res. 2009;1286:84–93. doi:10.1016/j.brainres.2009.06.079.PubMedCentralPubMedCrossRef

58.

Bi W, Yan J, Shi X, Yuva-Paylor LA, Antalffy BA, Goldman A, et al. Rai1 deficiency in mice causes learning impairment and motor dysfunction, whereas Rai1 heterozygous mice display minimal behavioral phenotypes. Hum Mol Genet. 2007;16(15):1802–13. doi:10.1093/hmg/ddm128.PubMedCrossRef

59.

de Rezende VB, Rosa DV, Comim CM, Magno LA, Rodrigues AL, Vidigal P, et al. NCS-1 deficiency causes anxiety and depressive-like behavior with impaired non-aversive memory in mice. Physiol Behav. 2014;130:91–8. doi:10.1016/j.physbeh.2014.03.005.PubMedCrossRef

60.

Bai J, Ramos RL, Ackman JB, Thomas AM, Lee RV, LoTurco JJ. RNAi reveals doublecortin is required for radial migration in rat neocortex. Nat Neurosci. 2003;6(12):1277–83. doi:10.1038/nn1153.PubMedCrossRef

61.

Corbo JC, Deuel TA, Long JM, LaPorte P, Tsai E, Wynshaw-Boris A, et al. Doublecortin is required in mice for lamination of the hippocampus but not the neocortex. J Neurosci. 2002;22(17):7548–57.PubMed

62.

Sorge RE, Martin LJ, Isbester KA, Sotocinal SG, Rosen S, Tuttle AH, et al. Olfactory exposure to males, including men, causes stress and related analgesia in rodents. Nat Methods. 2014;1–6.

63.

Spencer CM, Alekseyenko O, Hamilton SM, Thomas AM, Serysheva E, Yuva-Paylor LA, et al. Modifying behavioral phenotypes in Fmr1KO mice: genetic background differences reveal autistic-like responses. Autism Res. 2011;4(1):40–56.PubMedCentralPubMedCrossRef

64.

Jiang Y, Ehlers M. Modeling autism by SHANK gene mutations in mice. Neuron. 2013;78:8–27.PubMedCentralPubMedCrossRef

65.

Diamond DM, Campbell AM, Park CR, Halonen J, Zoladz PR. The temporal dynamics model of emotional memory processing: a synthesis on the neurobiological basis of stress-induced amnesia, flashbulb and traumatic memories, and the Yerkes-Dodson law. Neural Plasticity. 2007;2007:60803. doi:10.1155/2007/60803.PubMedCentralPubMedCrossRef

66.

Halpin B. Effects of arousal level on olfactory sensitivity. Percept Mot Skills. 1978;46(3 Pt 2):1095–102. doi:10.2466/pms.1978.46.3c.1095.PubMedCrossRef

67.

Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF, et al. Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci U S A. 2003;100(10):6186–91. doi:10.1073/pnas.0931309100.PubMedCentralPubMedCrossRef

68.

Cools R, D’Esposito M. Inverted-U-shaped dopamine actions on human working memory and cognitive control. Biol Psychiatry. 2011;69(12):e113–25. doi:10.1016/j.biopsych.2011.03.028.PubMedCentralPubMedCrossRef

69.

Diamond DM, Bennett MC, Fleshner M, Rose GM. Inverted-U relationship between the level of peripheral corticosterone and the magnitude of hippocampal primed burst potentiation. Hippocampus. 1992;2(4):421–30. doi:10.1002/hipo.450020409.PubMedCrossRef

70.

Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141(7):1117–34.PubMedCentralPubMedCrossRef

71.

Berg JM, Geschwind DH. Autism genetics: searching for specificity and convergence. Genome Biol. 2012;13(7):247. doi:10.1186/gb4034.PubMedCentralPubMedCrossRef

72.

Levitt P, Campbell DB. The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders. J Clin Invest. 2009;119(4):747–54. doi:10.1172/JCI37934.PubMedCentralPubMedCrossRef

73.

Sheng L, Ding X, Ferguson M, McCallister M, Rhoades R, Maguire M, et al. Prenatal polycyclic aromatic hydrocarbon exposure leads to behavioral deficits and downregulation of receptor tyrosine kinase. MET Toxicological Sci. 2010;118(2):625–34.CrossRef

74.

Volk HE, Kerin T, Lurmann F, Hertz-Picciotto I, McConnell R, Campbell DB. Autism spectrum disorder: interaction of air pollution with the MET receptor tyrosine kinase gene. Epidemiology. 2014;25(1):44–7. doi:10.1097/EDE.0000000000000030.PubMedCentralPubMedCrossRef

75.

Wu HH, Levitt P. Prenatal expression of MET receptor tyrosine kinase in the fetal mouse dorsal raphe nuclei and the visceral motor/sensory brainstem. Dev Neurosci. 2013;35(1):1–16. doi:10.1159/000346367.PubMedCentralPubMedCrossRef

Title: Complete or partial reduction of the Met receptor tyrosine kinase in distinct circuits differentially impacts mouse behavior
Authors: Barbara L. Thompson
Pat Levitt
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Journal of Neurodevelopmental Disorders / Issue 1/2015
Print ISSN: 1866-1947
Electronic ISSN: 1866-1955
DOI: https://doi.org/10.1186/s11689-015-9131-8

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Complete or partial reduction of the Met receptor tyrosine kinase in distinct circuits differentially impacts mouse behavior

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2015

CNTN6 copy number variations in 14 patients: a possible candidate gene for neurodevelopmental and neuropsychiatric disorders

Route knowledge and configural knowledge in typical and atypical development: a comparison of sparse and rich environments

Cerebral volumetric abnormalities in Neurofibromatosis type 1: associations with parent ratings of social and attention problems, executive dysfunction, and autistic mannerisms

Psychiatric disorders in adolescents and young adults with Down syndrome and other intellectual disabilities

Altered modulation of gamma oscillation frequency by speed of visual motion in children with autism spectrum disorders

Behavioral, cognitive, and adaptive development in infants with autism spectrum disorder in the first 2 years of life