Neurochemical Research

, Volume 44, Issue 6, pp 1410–1424 | Cite as

Inflammation in Traumatic Brain Injury: Roles for Toxic A1 Astrocytes and Microglial–Astrocytic Crosstalk

  • David P. Q. Clark
  • Victoria M. Perreau
  • Sandy R. Shultz
  • Rhys D. Brady
  • Enie Lei
  • Shilpi Dixit
  • Juliet M. Taylor
  • Philip M. BeartEmail author
  • Wah Chin Boon
Original Paper


Traumatic brain injury triggers neuroinflammation that may contribute to progressive neurodegeneration. We investigated patterns of recruitment of astrocytes and microglia to inflammation after brain trauma by firstly characterising expression profiles over time of marker genes following TBI, and secondly by monitoring glial morphologies reflecting inflammatory responses in a rat model of traumatic brain injury (i.e. the lateral fluid percussion injury). Gene expression profiles revealed early elevation of expression of astrocytic marker glial fibrillary acidic protein relative to microglial marker allograft inflammatory factor 1 (also known as ionized calcium-binding adapter molecule 1). Adult rat brains collected at day 7 after injury were processed for immunohistochemistry with allograft inflammatory factor 1, glial fibrillary acidic protein and complement C3 (marker of bad/disruptive astrocytic A1 phenotype). Astrocytes positive for glial fibrillary acidic protein and complement C3 were significant increased in the injured cortex and displayed more complex patterns of arbourisation with significantly increased bifurcations. Our observations suggested that traumatic brain injury changed the phenotype of microglia from a ramified appearance with long, thin, highly branched processes to a swollen amoeboid shape in the injured cortex. These findings suggest differential glial activation with astrocytes likely undergoing strategic changes in morphology and function. Whilst a detailed analysis is needed of temporal patterns of glial activation, ours is the first evidence of a role for the bad/disruptive astrocytic A1 phenotype in an open head model of traumatic brain injury.


Traumatic brain injury Inflammation Astrocyte Toxic phenotype Glial crosstalk 



Neurotoxic phenotype of reactive astrocytes


Neuroprotective phenotype of reactive astrocytes


Allograft inflammatory factor 1


Auditory cortex


Blood–brain barrier


Brain-derived neurotrophic factor


Complement component 3


Complement component 3 immunoreactive positive


Controlled cortical impact injury


Central nervous system


Chondroitin sulphate proteoglycan


Complement component 1q


Cluster of differentiation 68


Colony stimulating factor 1


Damage-associated molecular patterns


Disease-associated microglia




Lateral fluid percussion injury


Glial fibrillary acidic protein


Glial fibrillary acidic protein immunoreactive positive


Hydrochloric acid


Ionized calcium-binding adapter molecule 1




Neurotoxic phenotype of reactive microglia


Neuroprotective phenotype of reactive microglia


Normal donkey serum


Phosphate buffered saline


Region somatosensory cortex




Traumatic brain injury


Transforming growth factor beta 1


Tumor necrosis factor



PMB is pleased to contribute a paper to this Special Issue honouring Tony Turner who has been a colleague furthering the neurochemical cause via the Journal of Neurochemistry and internationally (ISN) and in Europe (ESN) for some 20 years. This work is partly funded by the J and M Nolan Family Trust. This work was supported by the Victorian Government through the Operational Infrastructure Scheme.


  1. 1.
    Johnson VE, Stewart W, Arena JD, Smith DH (2017) Traumatic brain injury as a trigger of neurodegeneration. Adv Neurobiol 15:383–400CrossRefGoogle Scholar
  2. 2.
    Loane DJ, Stoica BA, Faden AI (2015) Neuroprotection for traumatic brain injury. Handb Clin Neurol 127:343–366CrossRefGoogle Scholar
  3. 3.
    Faden AI, Wu J, Stoica BA, Loane DJ (2016) Progressive inflammation-mediated neurodegeneration after traumatic brain or spinal cord injury. Br J Pharmacol 173:681–691CrossRefGoogle Scholar
  4. 4.
    Karve IP, Taylor JM, Crack PJ (2016) The contribution of astrocytes and microglia to traumatic brain injury. Br J Pharmacol 173:692–702CrossRefGoogle Scholar
  5. 5.
    Fehily B, Fitzgerald M (2017) Repeated mild traumatic brain injury: potential mechanisms of damage. Cell Transplant 26:1131–1155CrossRefGoogle Scholar
  6. 6.
    Sun M, McDonald SJ, Brady RD, O’Brien TJ, Shultz SR (2018) The influence of immunological stressors on traumatic brain injury. Brain Behav Immun 69:618–628CrossRefGoogle Scholar
  7. 7.
    Ziebell JM, Morganti-Kossmann MC (2010) Involvement of pro- and anti-inflammatory cytokines and chemokines in the pathophysiology of traumatic brain injury. Neurotherapeutics 7:22–30CrossRefGoogle Scholar
  8. 8.
    Kelso ML, Gendelman HE (2014) Bridge between neuroimmunity and traumatic brain injury. Curr Pharm Des 20:4284–4298Google Scholar
  9. 9.
    Corps KN, Roth TL, McGavern DB (2015) Inflammation and neuroprotection in traumatic brain injury. JAMA Neurol 72:355–362CrossRefGoogle Scholar
  10. 10.
    Loane DJ, Byrnes KR (2010) Role of microglia in neurotrauma. Neurotherapeutics 7:66–77CrossRefGoogle Scholar
  11. 11.
    Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35CrossRefGoogle Scholar
  12. 12.
    Barres BA (2008) The mystery and magic of glia: a perspective on their roles in health and disease. Neuron 60:430–440CrossRefGoogle Scholar
  13. 13.
    Verkhratsky A, Zorec R, Rodriguez JJ, Parpura V (2017) Neuroglia: functional paralysis and reactivity in Alzheimer’s disease and other neurodegenerative pathologies. Adv Neurobiol 15:427–449CrossRefGoogle Scholar
  14. 14.
    Bao F, Shultz SR, Hepburn JD, Omana V, Weaver LC, Cain DP, Brown A (2012) A CD11d monoclonal antibody treatment reduces tissue injury and improves neurological outcome after fluid percussion brain injury in rats. J Neurotrauma 29:2375–2392CrossRefGoogle Scholar
  15. 15.
    Webster KM, Wright DK, Sun M, Semple BD, Ozturk E, Stein DG, O’Brien TJ, Shultz SR (2015) Progesterone treatment reduces neuroinflammation, oxidative stress and brain damage and improves long-term outcomes in a rat model of repeated mild traumatic brain injury. J Neuroinflamm 12:238CrossRefGoogle Scholar
  16. 16.
    Shultz SR, Sun M, Wright DK, Brady RD, Liu S, Beynon S, Schmidt SF, Kaye AH, Hamilton JA, O’Brien TJ, Grills BL, McDonald SJ (2015) Tibial fracture exacerbates traumatic brain injury outcomes and neuroinflammation in a novel mouse model of multitrauma. J Cereb Blood Flow Metab 35:1339–1347CrossRefGoogle Scholar
  17. 17.
    Webster KM, Sun M, Crack P, O’Brien TJ, Shultz SR, Semple BD (2017) Inflammation in epileptogenesis after traumatic brain injury. J Neuroinflamm 14:10CrossRefGoogle Scholar
  18. 18.
    Cafferty WB, Yang SH, Duffy PJ, Li S, Strittmatter SM (2007) Functional axonal regeneration through astrocytic scar genetically modified to digest chondroitin sulfate proteoglycans. J Neurosci 27:2176–2185CrossRefGoogle Scholar
  19. 19.
    Ridet JL, Malhotra SK, Privat A, Gage FH (1997) Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci 20:570–577CrossRefGoogle Scholar
  20. 20.
    Anderson MA, Burda JE, Ren Y, Ao Y, O’Shea TM, Kawaguchi R, Coppola G, Khakh BS, Deming TJ, Sofroniew MV (2016) Astrocyte scar formation aids central nervous system axon regeneration. Nature 532:195–200CrossRefGoogle Scholar
  21. 21.
    Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Münch AE, Chung WS, Peterson TC, Wilton DK, Frouin A, Napier BA, Panicker N, Kumar M, Buckwalter MS, Rowitch DH, Dawson VL, Dawson TM, Stevens B, Barres BA (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481–487CrossRefGoogle Scholar
  22. 22.
    Sewell DL, Nacewicz B, Liu F, Macvilay S, Erdei A, Lambris JD, Sandor M, Fabry Z (2004) Complement C3 and C5 play critical roles in traumatic brain cryoinjury: blocking effects on neutrophil extravasation by C5a receptor antagonist. J Neuroimmunol 155:55–63CrossRefGoogle Scholar
  23. 23.
    Loane DJ, Kumar A (2016) Microglia in the TBI brain: the good, the bad, and the dysregulated. Exp Neurol 275:316–327CrossRefGoogle Scholar
  24. 24.
    Kumar A, Alvarez-Croda DM, Stoica BA, Faden AI, Loane DJ (2016) Microglial/macrophage polarization dynamics following traumatic brain injury. J Neurotrauma 33:1732–1750CrossRefGoogle Scholar
  25. 25.
    Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318CrossRefGoogle Scholar
  26. 26.
    Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394CrossRefGoogle Scholar
  27. 27.
    Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, Giffard RG, Barres BA (2012) Genomic analysis of reactive astrogliosis. J Neurosci 32:6391–6410CrossRefGoogle Scholar
  28. 28.
    Burda JE, Sofroniew MV (2017) Seducing astrocytes to the dark side. Cell Res 27:726–727CrossRefGoogle Scholar
  29. 29.
    Natale JE, Ahmed F, Cernak I, Stoica B, Faden AI (2003) Gene expression profile changes are commonly modulated across models and species after traumatic brain injury. J Neurotrauma 20:907–927CrossRefGoogle Scholar
  30. 30.
    Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, Marshall KA, Phillippy KH, Sherman PM, Holko M, Yefanov A, Lee H, Zhang N, Robertson CL, Serova N, Davis S, Soboleva A (2013) NCBI GEO: archive for functional genomics data sets—update. Nucleic Acids Res 41:D991–D995CrossRefGoogle Scholar
  31. 31.
    Bolstad BM, Irizarry RA, Astrand M, Speed TP (2003) A comparison of normalization methods for high density oligonucleotide array data based on bias and variance. Bioinformatics 19:185–193CrossRefGoogle Scholar
  32. 32.
    RStudio Team (2015) RStudio: integrated development for R. RStudio, Inc., BostonGoogle Scholar
  33. 33.
    Wickham H (2009) ggplot2: elegant graphics for data analysis. Springer, New YorkCrossRefGoogle Scholar
  34. 34.
    Kent WJ (2002) BLAT—the BLAST-like alignment tool. Genome Res 12:656–664CrossRefGoogle Scholar
  35. 35.
    Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, Haussler D (2002) The human genome browser at UCSC. Genome Res 12:996–1006CrossRefGoogle Scholar
  36. 36.
    Shultz SR, Cardamone L, Liu YR, Hogan RE, Maccotta L, Wright DK, Zheng P, Koe A, Gregoire MC, Williams JP, Hicks RJ, Jones NC, Myers DE, O’Brien TJ, Bouilleret V (2013) Can structural or functional changes following traumatic brain injury in the rat predict epileptic outcome? Epilepsia 54:1240–1250CrossRefGoogle Scholar
  37. 37.
    Johnstone VP, Wright DK, Wong KK, O’Brien TJ, Rajan R, Shultz S (2015) Experimental traumatic brain injury results in long-term recovery of functional responsiveness in sensory cortex but persisting structural changes and sensorimotor, cognitive, and emotional deficits. J Neurotrauma 32:1333–1346CrossRefGoogle Scholar
  38. 38.
    Wright DK, Liu S, van der Poel C, McDonald SJ, Brady RD, Taylor L, Yang L, Gardner AJ, Ordidge R, O’Brien TJ, Johnston LA, Shultz SR (2017) Traumatic brain injury results in cellular, structural and functional changes resembling motor neuron disease. Cereb Cortex 27:4503–4515Google Scholar
  39. 39.
    Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates. Academic Press, San DiegoGoogle Scholar
  40. 40.
    Ziebell JM, Taylor SE, Cao T, Harrison JL, Lifshitz J (2012) Rod microglia: elongation, alignment, and coupling to form trains across the somatosensory cortex after experimental diffuse brain injury. J Neuroinflamm 9:247CrossRefGoogle Scholar
  41. 41.
    Gundersen HJ, Jensen EB (1987) The efficiency of systematic sampling in stereology and its prediction. J Microsc 147:229–263CrossRefGoogle Scholar
  42. 42.
    Schmitz C, Hof PR (2005) Design-based stereology in neuroscience. Neuroscience 130:813–831CrossRefGoogle Scholar
  43. 43.
    Lau CL, Perreau VM, Chen MJ, Cate HS, Merlo D, Cheung NS, O’Shea RD, Beart PM (2012) Transcriptomic profiling of astrocytes treated with the Rho kinase inhibitor fasudil reveals cytoskeletal and pro-survival responses. J Cell Physiol 227:1199–1211CrossRefGoogle Scholar
  44. 44.
    Namihira M, Nakashima K (2013) Mechanisms of astrocytogenesis in the mammalian brain. Curr Opin Neurobiol 23:921–927CrossRefGoogle Scholar
  45. 45.
    Sofroniew MV (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 32:638–647CrossRefGoogle Scholar
  46. 46.
    Lenz KM, Nelson LH (2018) Microglia and beyond: innate immune cells as regulators of brain development and behavioral function. Front Immunol 9:698CrossRefGoogle Scholar
  47. 47.
    Colton CA (2009) Heterogeneity of microglial activation in the innate immune response in the brain. J Neuroimmune Pharmacol 4:399–418CrossRefGoogle Scholar
  48. 48.
    Sarlus H, Heneka MT (2017) Microglia in Alzheimer’s disease. J Clin Investig 127:3240–3249CrossRefGoogle Scholar
  49. 49.
    Ransohoff RM (2016) A polarizing question: do M1 and M2 microglia exist? Nat Neurosci 19:987–991CrossRefGoogle Scholar
  50. 50.
    Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I (2017) A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169:1276–1290CrossRefGoogle Scholar
  51. 51.
    Hickman SE, Kingery ND, Ohsumi TK, Borowsky ML, Wang LC, Means TK, El Khoury J (2013) The microglial sensome revealed by direct RNA sequencing. Nat Neurosci 16:1896–1905CrossRefGoogle Scholar
  52. 52.
    Deczkowska A, Keren-Shaul H, Weiner A, Colonna M, Schwartz M, Amit I (2018) Disease-associated microglia: a universal immune sensor of neurodegeneration. Cell 173:1073–1081CrossRefGoogle Scholar
  53. 53.
    Grabert K, Michoel T, Karavolos MH, Clohisey S, Baillie JK, Stevens MP, Freeman TC, Summers KM, McColl BW (2016) Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat Neurosci 19:504–516CrossRefGoogle Scholar
  54. 54.
    Jassam YN, Izzy S, Whalen M, McGavern DB, El Khoury J (2017) Neuroimmunology of traumatic brain injury: time for a paradigm shift. Neuron 95:1246–1265CrossRefGoogle Scholar
  55. 55.
    Ramlackhansingh AF, Brooks DJ, Greenwood RJ, Bose SK, Turkheimer FE, Kinnunen KM, Gentleman S, Heckemann RA, Gunanayagam K, Gelosa G, Sharp DJ (2011) Inflammation after trauma: microglial activation and traumatic brain injury. Ann Neurol 70:374–383CrossRefGoogle Scholar
  56. 56.
    Fourgeaud L, Través PG, Tufail Y, Leal-Bailey H, Lew ED, Burrola PG, Callaway P, Zagórska A, Rothlin CV, Nimmerjahn A, Lemke G (2016) TAM receptors regulate multiple features of microglial physiology. Nature 532:240–244CrossRefGoogle Scholar
  57. 57.
    Roth TL, Nayak D, Atanasijevic T, Koretsky AP, Latour LL, McGavern DB (2014) Transcranial amelioration of inflammation and cell death after brain injury. Nature 505:223–228CrossRefGoogle Scholar
  58. 58.
    Shitaka Y, Tran HT, Bennett RE, Sanchez L, Levy MA, Dikranian K, Brody DL (2011) Repetitive closed-skull traumatic brain injury in mice causes persistent multifocal axonal injury and microglial reactivity. J Neuropathol Exp Neurol 70:551–567CrossRefGoogle Scholar
  59. 59.
    Mannix R, Meehan WP, Mandeville J, Grant PE, Gray T, Berglass J, Zhang J, Bryant J, Rezaie S, Chung JY, Peters NV, Lee C, Tien LW, Kaplan DL, Feany M, Whalen M (2013) Clinical correlates in an experimental model of repetitive mild brain injury. Ann Neurol 74:65–75CrossRefGoogle Scholar
  60. 60.
    Huber BR, Meabon JS, Hoffer ZS, Zhang J, Hoekstra JG, Pagulayan KF, McMillan PJ, Mayer CL, Banks WA, Kraemer BC, Raskind MA, McGavern DB, Peskind ER, Cook DG (2016) Blast exposure causes dynamic microglial/macrophage responses and microdomains of brain microvessel dysfunction. Neuroscience 319:206–220CrossRefGoogle Scholar
  61. 61.
    Meng Q, Zhuang Y, Ying Z, Agrawal R, Yang X, Gomez-Pinilla F (2017) Traumatic brain injury induces genome-wide transcriptomic, methylomic, and network perturbations in brain and blood predicting neurological disorders. EBioMedicine 16:184–194CrossRefGoogle Scholar
  62. 62.
    Chiu CC, Liao YE, Yang LY, Wang JY, Tweedie D, Karnati HK, Greig NH, Wang JY (2016) Neuroinflammation in animal models of traumatic brain injury. J Neurosci Methods 272:49CrossRefGoogle Scholar
  63. 63.
    Donat CK, Scott G, Gentleman SM, Sastre M (2017) Microglial activation in traumatic brain injury. Front Aging Neurosci 9:208CrossRefGoogle Scholar
  64. 64.
    Bouvier DS, Murai KK (2015) Synergistic actions of microglia and astrocytes in the progression of Alzheimer’s disease. J Alzheimers Dis 45:1001–1014CrossRefGoogle Scholar
  65. 65.
    Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8:752–758CrossRefGoogle Scholar
  66. 66.
    Kim JV, Dustin ML (2006) Innate response to focal necrotic injury inside the blood-brain barrier. J Immunol 177:5269–5277CrossRefGoogle Scholar
  67. 67.
    Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, Sofroniew MV (2004) Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci 24:2143–2155CrossRefGoogle Scholar
  68. 68.
    Herrmann JE, Imura T, Song B, Qi J, Ao Y, Nguyen TK, Korsak RA, Takeda K, Akira S, Sofroniew MV (2008) STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J Neurosci 28:7231–7243CrossRefGoogle Scholar
  69. 69.
    Boisvert MM, Erikson GA, Shokhirev MN, Allen NJ (2018) The aging astrocyte transcriptome from multiple regions of the mouse brain. Cell Rep 22:269–285CrossRefGoogle Scholar
  70. 70.
    Clarke LE, Liddelow SA, Chakraborty C, Münch AE, Heiman M, Barres BA (2018) Normal aging induces A1-like astrocyte reactivity. Proc Natl Acad Sci USA 115:E1896–E1905CrossRefGoogle Scholar
  71. 71.
    Yun SP, Kam TI, Panicker N, Kim S, Oh Y, Park JS, Kwon SH, Park YJ, Karuppagounder SS, Park H, Kim S, Oh N, Kim NA, Lee S, Brahmachari S, Mao X, Lee JH, Kumar M, An D, Kang SU, Lee Y, Lee KC, Na DH, Kim D, Lee SH, Roschke VV, Liddelow SA, Mari Z, Barres BA, Dawson VL, Lee S, Dawson TM, Ko HS (2018) Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nat Med 24:931–938CrossRefGoogle Scholar
  72. 72.
    Araque A, Parpura V, Sanzgiri RP, Haydon PG (1999) Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 22:208–215CrossRefGoogle Scholar
  73. 73.
    Sofroniew MV (2015) Astrocyte barriers to neurotoxic inflammation. Nat Rev Neurosci 16:249–263CrossRefGoogle Scholar
  74. 74.
    Beart PM, O’Shea RD (2007) Transporters for L-glutamate: an update on their molecular pharmacology and pathological involvement. Br J Pharmacol 150:5–17CrossRefGoogle Scholar
  75. 75.
    Martinez-Lozada Z, Guillem AM, Robinson MB (2016) Transcriptional regulation of glutamate transporters: from extracellular signals to transcription factors. Adv Pharmacol 76:103–145CrossRefGoogle Scholar
  76. 76.
    Panickar KS, Norenberg MD (2005) Astrocytes in cerebral ischemic injury: morphological and general considerations. Glia 50:287–298CrossRefGoogle Scholar
  77. 77.
    Schipke CG, Boucsein C, Ohlemeyer C, Kirchhoff F, Kettenmann H (2002) Astrocyte Ca2+ waves trigger responses in microglial cells in brain slices. FASEB J 16:255–257CrossRefGoogle Scholar
  78. 78.
    Verderio C, Matteoli M (2001) ATP mediates calcium signaling between astrocytes and microglial cells: modulation by IFN-gamma. J Immunol 166:6383–6391CrossRefGoogle Scholar
  79. 79.
    Norden DM, Fenn AM, Dugan A, Godbout JP (2014) TGFß produced by IL-10 redirected astrocytes attenuates microglial activation. Glia 62:881–895CrossRefGoogle Scholar
  80. 80.
    Li L, Lundkvist A, Andersson D, Wilhelmsson U, Nagai N, Pardo AC, Nodin C, Ståhlberg A, Aprico K, Larsson K, Yabe T, Moons L, Fotheringham A, Davies I, Carmeliet P, Schwartz JP, Pekna M, Kubista M, Blomstrand F, Maragakis N, Nilsson M, Pekny M (2008) Protective role of reactive astrocytes in brain ischemia. J Cereb Blood Flow Metab 28:468–481CrossRefGoogle Scholar
  81. 81.
    Abeysinghe HC, Phillips EL, Chin-Cheng H, Beart PM, Roulston CL (2016) Modulating astrocyte transition after stroke to promote brain rescue and functional recovery: emerging targets include rho kinase. Int J Mol Sci 17:288–305CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • David P. Q. Clark
    • 1
  • Victoria M. Perreau
    • 1
  • Sandy R. Shultz
    • 2
    • 3
  • Rhys D. Brady
    • 2
    • 3
  • Enie Lei
    • 1
  • Shilpi Dixit
    • 1
  • Juliet M. Taylor
    • 4
  • Philip M. Beart
    • 1
    • 4
    Email author
  • Wah Chin Boon
    • 1
  1. 1.The Florey Institute of Neuroscience and Mental HealthParkvilleAustralia
  2. 2.Department of Neuroscience, Central Clinical SchoolMonash UniversityMelbourneAustralia
  3. 3.Department of Medicine, The Royal Melbourne HospitalThe University of MelbourneParkvilleAustralia
  4. 4.Department of Pharmacology & TherapeuticsUniversity of MelbourneParkvilleAustralia

Personalised recommendations