Skip to main content

Advertisement

Log in

Reduced Glutamate Release in Adult BTBR Mouse Model of Autism Spectrum Disorder

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Autism spectrum disorder (ASD) is a developmental disorder characterized by impairments in social and communication abilities, as well as by restricted and repetitive behaviors. The BTBR T + Itpr3 tf (BTBR) mice have emerged as a well characterized and widely used mouse model of a range of ASD-like phenotype, showing deficiencies in social behaviors and unusual ultrasonic vocalizations as well as increased repetitive self-grooming. However, the inherited neurobiological changes that lead to ASD-like behaviors in these mice are incompletely known and still under active investigation. The aim of this study was to further evaluate the structure and neurotransmitter release of the glutamatergic synapse in BTBR mice. C57BL/6J (B6) mice were used as a control strain because of their high level of sociability. The important results showed that the evoked glutamate release in the cerebral cortex of BTBR mice was significantly lower than in B6 mice. And the level of vesicle docking-related protein Syntaxin-1A was reduced in BTBR mice. However, no significant changes were observed in the number of glutamatergic synapse, level of synaptic proteins, density of dendritic spine and postsynaptic density between BTBR mice and B6 mice. Overall, our results suggest that abnormal vesicular glutamate activity may underlie the ASD relevant pathology in the BTBR mice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Pasciuto E, Borrie SC, Kanellopoulos AK, Santos AR, Cappuyns E, D’Andrea L, Pacini L, Bagni C (2015) Autism Spectrum Disorders: translating human deficits into mouse behavior. Neurobiol Learn Mem 124:71–87

    Article  CAS  PubMed  Google Scholar 

  2. Silverman JL, Tolu SS, Barkan CL, Crawley JN (2010) Repetitive self-grooming behavior in the BTBR mouse model of autism is blocked by the mGluR5 antagonist MPEP. Neuropsychopharmacology 35:976–989

    Article  CAS  PubMed  Google Scholar 

  3. Silverman JL, Oliver CF, Karras MN, Gastrell PT, Crawley JN (2013) AMPAKINE enhancement of social interaction in the BTBR mouse model of autism. Neuropharmacology 64:268–282

    Article  CAS  PubMed  Google Scholar 

  4. Chadman KK (2011) Fluoxetine but not risperidone increases sociability in the BTBR mouse model of autism. Pharmacology Biochemistry Behavior 97:586–594

    Article  CAS  Google Scholar 

  5. Segal-Gavish H, Karvat G, Barak N, Barzilay R, Ganz J, Edry L, Aharony I, Offen D, Kimchi T (2016) Mesenchymal stem cell transplantation promotes neurogenesis and ameliorates autism related behaviors in BTBR mice. Autism Res 9:17–32

    Article  PubMed  Google Scholar 

  6. Hagen E, Shprung D, Minakova E, Washington J 3rd, Kumar U, Shin D, Sankar R, Mazarati A (2015) Autism-like behavior in BTBR mice is improved by electroconvulsive therapy. Neurotherapeutics 12:657–666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ellegood J, Babineau BA, Henkelman RM, Lerch JP, Crawley JN (2013) Neuroanatomical analysis of the BTBR mouse model of autism using magnetic resonance imaging and diffusion tensor imaging. NeuroImage 70:288–300

    Article  PubMed  Google Scholar 

  8. Hwang SR, Kim CY, Shin KM, Jo JH, Kim HA, Heo Y (2015) Altered expression levels of neurodevelopmental proteins in fetal brains of BTBR T+tf/J mice with autism-like behavioral characteristics. J Toxicol Environ Health A 78:516–523

    Article  CAS  PubMed  Google Scholar 

  9. Ebrahimi-Fakhari D, Sahin M (2015) Autism and the synapse: emerging mechanisms and mechanism-based therapies. Curr Opin Neurol 28:91–102

    Article  CAS  PubMed  Google Scholar 

  10. Volk L, Chiu SL, Sharma K, Huganir RL (2015) Glutamate synapses in human cognitive disorders. Annu Rev Neurosci 38:127–149

    Article  CAS  PubMed  Google Scholar 

  11. Tebartz van Elst L, Maier S, Fangmeier T, Endres D, Mueller GT, Nickel K, Ebert D, Lange T, Hennig J, Biscaldi M, Riedel A, Perlov E (2014) Disturbed cingulate glutamate metabolism in adults with high-functioning autism spectrum disorder: evidence in support of the excitatory/inhibitory imbalance hypothesis. Mol Psychiatry 19:1314–1325

    Article  CAS  PubMed  Google Scholar 

  12. Fatemi SH, Halt AR, Stary JM, Kanodia R, Schulz SC, Realmuto GR (2002) Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol Psychiatry 52:805–810

    Article  CAS  PubMed  Google Scholar 

  13. Peca J, Feliciano C, Ting JT, Wang W, Wells MF, Venkatraman TN, Lascola CD, Fu Z, Feng G (2011) Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 472:437–442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Stephenson DT, O’Neill SM, Narayan S, Tiwari A, Arnold E, Samaroo HD, Du F, Ring RH, Campbell B, Pletcher M, Vaidya VA, Morton D (2011) Histopathologic characterization of the BTBR mouse model of autistic-like behavior reveals selective changes in neurodevelopmental proteins and adult hippocampal neurogenesis. Mol Autism 2:7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jasien JM, Daimon CM, Wang R, Shapiro BK, Martin B, Maudsley S (2014) The effects of aging on the BTBR mouse model of autism spectrum disorder. Front Aging Neurosci 6:225

    Article  PubMed  PubMed Central  Google Scholar 

  16. Wei H, Ding C, Jin G, Yin H, Liu J, Hu F (2015) Abnormal glutamate release in aged BTBR mouse model of autism. Int J Clin Exp Pathol 8:10689–10697

    PubMed  PubMed Central  Google Scholar 

  17. Yang M, Clarke AM, Crawley JN (2009) Postnatal lesion evidence against a primary role for the corpus callosum in mouse sociability. Eur J Neurosci 29:1663–1677

    Article  PubMed  PubMed Central  Google Scholar 

  18. McFarlane HG, Kusek GK, Yang M, Phoenix JL, Bolivar VJ, Crawley JN (2008) Autism-like behavioral phenotypes in BTBR T+tf/J mice. Genes Brain Behav 7:152–163

    Article  CAS  PubMed  Google Scholar 

  19. Nadler JJ, Moy SS, Dold G, Trang D, Simmons N, Perez A, Young NB, Barbaro RP, Piven J, Magnuson TR, Crawley JN (2004) Automated apparatus for quantitation of social approach behaviors in mice. Genes Brain Behav 3:303–314

    Article  CAS  PubMed  Google Scholar 

  20. Ippolito DM, Eroglu C (2010) Quantifying synapses: an immunocytochemistry-based assay to quantify synapse number. J Vis Exp. doi:10.3791/2270

    PubMed  PubMed Central  Google Scholar 

  21. Barr DJ, Ostermeyer-Fay AG, Matundan RA, Brown DA (2008) Clathrin-independent endocytosis of ErbB2 in geldanamycin-treated human breast cancer cells. J Cell Sci 121:3155–3166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wei H, Chadman KK, McCloskey DP, Sheikh AM, Malik M, Brown WT, Li X (2012) Brain IL-6 elevation causes neuronal circuitry imbalances and mediates autism-like behaviors. Biochimi Biophys Acta 1822:831–842

    Article  CAS  Google Scholar 

  23. Jaworski J, Kapitein LC, Gouveia SM, Dortland BR, Wulf PS, Grigoriev I, Camera P, Spangler SA, Di Stefano P, Demmers J, Krugers H, Defilippi P, Akhmanova A, Hoogenraad CC (2009) Dynamic microtubules regulate dendritic spine morphology and synaptic plasticity. Neuron 61:85–100

    Article  CAS  PubMed  Google Scholar 

  24. Shen HW, Toda S, Moussawi K, Bouknight A, Zahm DS, Kalivas PW (2009) Altered dendritic spine plasticity in cocaine-withdrawn rats. J Neurosci 29:2876–2884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wei H, Malik M, Sheikh AM, Merz G, Brown WT, Li X (2011) Abnormal cell properties and down-regulated FAK-Src complex signaling in B lymphoblasts of autistic subjects. Am J Pathol 179:66–74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Schwartz-Bloom RD, Engblom AC, Akerman KE, Inglefield JR (2001) Measurement of chloride movement in neuronal preparations. Curr Protoc Neurosci Chap. 7:Unit 7.10

  27. Christopherson KS, Ullian EM, Stokes CC, Mullowney CE, Hell JW, Agah A, Lawler J, Mosher DF, Bornstein P, Barres BA (2005) Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120:421–433

    Article  CAS  PubMed  Google Scholar 

  28. Villasana LE, Klann E, Tejada-Simon MV (2006) Rapid isolation of synaptoneurosomes and postsynaptic densities from adult mouse hippocampus. J Neurosci Methods 158:30–36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nicholls DG, Sihra TS, Sanchez-Prieto J (1987) Calcium-dependent and -independent release of glutamate from synaptosomes monitored by continuous fluorometry. J Neurochem 49:50–57

    Article  CAS  PubMed  Google Scholar 

  30. Sim AT, Herd L, Proctor DT, Baldwin ML, Meunier FA, Rostas JA (2006) High throughput analysis of endogenous glutamate release using a fluorescence plate reader. J Neurosci Methods 153:43–47

    Article  CAS  PubMed  Google Scholar 

  31. Sheng M, Kim E (2011) The postsynaptic organization of synapses. Cold Spring Harb Perspect Biol 3. doi:10.1101/cshperspect.a005678

  32. Hollingsworth EB, McNeal ET, Burton JL, Williams RJ, Daly JW, Creveling CR (1985) Biochemical characterization of a filtered synaptoneurosome preparation from guinea pig cerebral cortex: cyclic adenosine 3′:5′-monophosphate-generating systems, receptors, and enzymes. J Neurosci 5:2240–2253

    CAS  PubMed  Google Scholar 

  33. Moy SS, Nadler JJ, Young NB, Perez A, Holloway LP, Barbaro RP, Barbaro JR, Wilson LM, Threadgill DW, Lauder JM, Magnuson TR, Crawley JN (2007) Mouse behavioral tasks relevant to autism: phenotypes of 10 inbred strains. Behav Brain Res 176:4–20

    Article  PubMed  Google Scholar 

  34. Wei H, Alberts I, Li X (2013) Brain IL-6 and autism. Neuroscience 252:320–325

    Article  CAS  PubMed  Google Scholar 

  35. Canitano R (2007) Epilepsy in autism spectrum disorders. Eur Child Adolesc Psychiatry 16:61–66

    Article  PubMed  Google Scholar 

  36. Tabuchi K, Blundell J, Etherton MR, Hammer RE, Liu X, Powell CM, Sudhof TC (2007) A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 318:71–76

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hutsler JJ, Zhang H (2010) Increased dendritic spine densities on cortical projection neurons in autism spectrum disorders. Brain Res 1309:83–94

    Article  CAS  PubMed  Google Scholar 

  38. Irwin SA, Patel B, Idupulapati M, Harris JB, Crisostomo RA, Larsen BP, Kooy F, Willems PJ, Cras P, Kozlowski PB, Swain RA, Weiler IJ, Greenough WT (2001) Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: a quantitative examination. Am J Med Genet 98:161–167

    Article  CAS  PubMed  Google Scholar 

  39. Han S, Tai C, Jones CJ, Scheuer T, Catterall WA (2014) Enhancement of inhibitory neurotransmission by GABAA receptors having alpha2,3-subunits ameliorates behavioral deficits in a mouse model of autism. Neuron 81:1282–1289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Gogolla N, Takesian AE, Feng G, Fagiolini M, Hensch TK (2014) Sensory integration in mouse insular cortex reflects GABA circuit maturation. Neuron 83:894–905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kaiser LG, Schuff N, Cashdollar N, Weiner MW (2005) Age-related glutamate and glutamine concentration changes in normal human brain: 1H MR spectroscopy study at 4T. Neurobiol Aging 26:665–672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hackett JT, Ueda T (2015) Glutamate Release. Neurochem Res 40:2443–2460

    Article  CAS  PubMed  Google Scholar 

  43. Pfeffer SR (1996) Transport vesicle docking: SNAREs and associates. Annu Rev Cell Dev Biol 12:441–461

    Article  CAS  PubMed  Google Scholar 

  44. Wei H, Ma Y, Liu J, Ding C, Hu F, Yu L (2016) Proteomic analysis of cortical brain tissue from the BTBR mouse model of autism: evidence for changes in STOP and myelin-related proteins. Neuroscience 312:26–34

    Article  CAS  PubMed  Google Scholar 

  45. Brenner E, Sonnewald U, Schweitzer A, Andrieux A, Nehlig A (2007) Hypoglutamatergic activity in the STOP knockout mouse: a potential model for chronic untreated schizophrenia. J Neurosci Res 85:3487–3493

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from National Natural Science Foundation of China (No. 81201061), the Ministry of Human Resources and Social Security of China (No. 2014), Shanxi Scholarship Council of China (No. 2013-124), Natural Science Foundation of Shanxi (No. 2013021036-2) and Outstanding Youth Talents Program of Shanxi Province.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hongen Wei.

Ethics declarations

Conflict of Interest

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wei, H., Ma, Y., Ding, C. et al. Reduced Glutamate Release in Adult BTBR Mouse Model of Autism Spectrum Disorder. Neurochem Res 41, 3129–3137 (2016). https://doi.org/10.1007/s11064-016-2035-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-016-2035-5

Keywords

Navigation