Skip to main content
Log in

Decoding Hippocampal Signaling Deficits After Traumatic Brain Injury

  • Review Article
  • Published:
Translational Stroke Research Aims and scope Submit manuscript

Abstract

There are more than 3.17 million people coping with long-term disabilities due to traumatic brain injury (TBI) in the United States. The majority of TBI research is focused on developing acute neuroprotective treatments to prevent or minimize these long-term disabilities. Therefore, chronic TBI survivors represent a large, underserved population that could significantly benefit from a therapy that capitalizes on the endogenous recovery mechanisms occurring during the weeks to months following brain trauma. Previous studies have found that the hippocampus is highly vulnerable to brain injury, in both experimental models of TBI and during human TBI. Although often not directly mechanically injured by the head injury, in the weeks to months following TBI, the hippocampus undergoes atrophy and exhibits deficits in long-term potentiation (LTP), a persistent increase in synaptic strength that is considered to be a model of learning and memory. Decoding the chronic hippocampal LTP and cell signaling deficits after brain trauma will provide new insights into the molecular mechanisms of hippocampal-dependent learning impairments caused by TBI and facilitate the development of effective therapeutic strategies to improve hippocampal-dependent learning for chronic survivors of TBI.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Faul M, Xu L, Wald MM, Coronado VG. Traumatic brain injury in the United States: emergency department visits, hospitalizations and deaths. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control. 2010;Atlanta, GA.

  2. Maas AI, Stocchetti N, Bullock R. Moderate and severe traumatic brain injury in adults. Lancet Neurol. 2008;7:728–41.

    PubMed  Google Scholar 

  3. Herman ST. Epilepsy after brain insult: targeting epileptogenesis. Neurology. 2002;59:S21–6.

    PubMed  Google Scholar 

  4. Holsinger T, Steffens DC, Phillips C, Helms MJ, Havlik RJ, Breitner JC, et al. Head injury in early adulthood and the lifetime risk of depression. Arch Gen Psychiatry. 2002;59:17–22.

    PubMed  Google Scholar 

  5. Plassman BL, Havlik RJ, Steffens DC, Helms MJ, Newman TN, Drosdick D, et al. Documented head injury in early adulthood and risk of Alzheimer's disease and other dementias. Neurology. 2000;55:1158–66.

    PubMed  CAS  Google Scholar 

  6. Selassie AW, McCarthy ML, Ferguson PL, Tian J, Langlois JA. Risk of posthospitalization mortality among persons with traumatic brain injury, South Carolina 1999–2001. J Head Trauma Rehabil. 2005;20:257–69.

    PubMed  Google Scholar 

  7. Horner MD, Ferguson PL, Selassie AW, Labbate LA, Kniele K, Corrigan JD. Patterns of alcohol use 1 year after traumatic brain injury: a population-based, epidemiological study. J Int Neuropsychol Soc. 2005;11:322–30.

    PubMed  Google Scholar 

  8. Slaughter B, Fann JR, Ehde D. Traumatic brain injury in a county jail population: prevalence, neuropsychological functioning and psychiatric disorders. Brain Inj. 2003;17:731–41.

    PubMed  Google Scholar 

  9. Christensen BK, Colella B, Inness E, Hebert D, Monette G, Bayley M, et al. Recovery of cognitive function after traumatic brain injury: a multilevel modeling analysis of Canadian outcomes. Arch Phys Med Rehabil. 2008;89:S3–S15.

    PubMed  Google Scholar 

  10. Olver JH, Ponsford JL, Curran CA. Outcome following traumatic brain injury: a comparison between 2 and 5 years after injury. Brain Inj. 1996;10:841–8.

    PubMed  CAS  Google Scholar 

  11. Zaloshnja E, Miller T, Langlois JA, Selassie AW. Prevalence of long-term disability from traumatic brain injury in the civilian population of the United States, 2005. J Head Trauma Rehabil. 2008;23:394–400.

    PubMed  Google Scholar 

  12. Serra-Grabulosa JM, Junque C, Verger K, Salgado-Pineda P, Maneru C, Mercader JM. Cerebral correlates of declarative memory dysfunctions in early traumatic brain injury. J Neurol Neurosurg Psychiatry. 2005;76:129–31.

    PubMed  CAS  Google Scholar 

  13. Mathias JL, Mansfield KM. Prospective and declarative memory problems following moderate and severe traumatic brain injury. Brain Inj. 2005;19:271–82.

    PubMed  CAS  Google Scholar 

  14. Whyte J, Polansky M, Cavallucci C, Fleming M, Lhulier J, Coslett HB. Inattentive behavior after traumatic brain injury. J Int Neuropsychol Soc. 1996;2:274–81.

    PubMed  CAS  Google Scholar 

  15. McAllister TW, Flashman LA, Sparling MB, Saykin AJ. Working memory deficits after traumatic brain injury: catecholaminergic mechanisms and prospects for treatment — a review. Brain Inj. 2004;18:331–50.

    PubMed  Google Scholar 

  16. Tomaiuolo F, Carlesimo GA, Di Paola M, Petrides M, Fera F, Bonanni R, et al. Gross morphology and morphometric sequelae in the hippocampus, fornix, and corpus callosum of patients with severe non-missile traumatic brain injury without macroscopically detectable lesions: a T1 weighted MRI study. J Neurol Neurosurg Psychiatry. 2004;75:1314–22.

    PubMed  CAS  Google Scholar 

  17. Tate DF, Bigler ED. Fornix and hippocampal atrophy in traumatic brain injury. Learn Mem. 2000;7:442–6.

    PubMed  CAS  Google Scholar 

  18. Kotapka MJ, Graham DI, Adams JH, Gennarelli TA. Hippocampal pathology in fatal non-missile human head injury. Acta Neuropathol (Berl). 1992;83:530–4.

    CAS  Google Scholar 

  19. Bigler ED, Anderson CV, Blatter DD. Temporal lobe morphology in normal aging and traumatic brain injury. Am J Neuroradiol. 2002;23:255–66.

    PubMed  Google Scholar 

  20. Smith DH, Okiyama K, Thomas MJ, Claussen B, McIntosh TK. Evaluation of memory dysfunction following experimental brain injury using the Morris water maze. J Neurotrauma. 1991;8:259–69.

    PubMed  CAS  Google Scholar 

  21. Pierce JE, Smith DH, Trojanowski JQ, McIntosh TK. Enduring cognitive, neurobehavioral and histopathological changes persist for up to one year following severe experimental brain injury in rats. Neuroscience. 1998;87:359–69.

    PubMed  CAS  Google Scholar 

  22. Dash PK, Moore AN, Dixon CE. Spatial memory deficits, increased phosphorylation of the transcription factor CREB, and induction of the AP-1 complex following experimental brain injury. J Neurosci. 1995;15:2030–9.

    PubMed  CAS  Google Scholar 

  23. Griesbach GS, Hovda DA, Molteni R, Wu A, Gomez-Pinilla F. Voluntary exercise following traumatic brain injury: brain-derived neurotrophic factor upregulation and recovery of function. Neuroscience. 2004;125:129–39.

    PubMed  CAS  Google Scholar 

  24. Scheff SW, Baldwin SA, Brown RW, Kraemer PJ. Morris water maze deficits in rats following traumatic brain injury: lateral controlled cortical impact. J Neurotrauma. 1997;14:615–27.

    PubMed  CAS  Google Scholar 

  25. Sanders MJ, Dietrich WD, Green EJ. Cognitive function following traumatic brain injury: effects of injury severity and recovery period in a parasagittal fluid-percussive injury model. J Neurotrauma. 1999;16:915–25.

    PubMed  CAS  Google Scholar 

  26. Bramlett HM, Green EJ, Dietrich WD. Hippocampally dependent and independent chronic spatial navigational deficits following parasagittal fluid percussion brain injury in the rat. Brain Res. 1997;762:195–202.

    PubMed  CAS  Google Scholar 

  27. Smith DH, Chen XH, Xu BN, McIntosh TK, Gennarelli TA, Meaney DF. Characterization of diffuse axonal pathology and selective hippocampal damage following inertial brain trauma in the pig. J Neuropathol Exp Neurol. 1997;56:822–34.

    PubMed  CAS  Google Scholar 

  28. Bramlett HM, Dietrich WD. Quantitative structural changes in white and gray matter 1 year following traumatic brain injury in rats. Acta Neuropathol (Berl). 2002;103:607–14.

    Google Scholar 

  29. Tran LD, Lifshitz J, Witgen BM, Schwarzbach E, Cohen AS, Grady MS. Response of the contralateral hippocampus to lateral fluid percussion brain injury. J Neurotrauma. 2006;23:1330–42.

    PubMed  Google Scholar 

  30. Maxwell WL, Dhillon K, Harper L, Espin J, MacIntosh TK, Smith DH, et al. There is differential loss of pyramidal cells from the human hippocampus with survival after blunt head injury. J Neuropathol Exp Neurol. 2003;62:272–9.

    PubMed  CAS  Google Scholar 

  31. Scheff SW, Price DA, Hicks RR, Baldwin SA, Robinson S, Brackney C. Synaptogenesis in the hippocampal CA1 field following traumatic brain injury. J Neurotrauma. 2005;22:719–32.

    PubMed  CAS  Google Scholar 

  32. Grady MS, Charleston JS, Maris D, Witgen BM, Lifshitz J. Neuronal and glial cell number in the hippocampus after experimental traumatic brain injury: analysis by stereological estimation. J Neurotrauma. 2003;20:929–41.

    PubMed  Google Scholar 

  33. Witgen BM, Lifshitz J, Smith ML, Schwarzbach E, Liang SL, Grady MS, et al. Regional hippocampal alteration associated with cognitive deficit following experimental brain injury: a systems, network and cellular evaluation. Neuroscience. 2005;133:1–15.

    PubMed  CAS  Google Scholar 

  34. Campbell JN, Churn SB, Register D. Traumatic brain injury causes an FK506-sensitive loss and an overgrowth of dendritic spines in rat forebrain. J Neurotrauma. 2011. doi:10.1089/neu.2011.1761.

  35. Golarai G, Greenwood AC, Feeney DM, Connor JA. Physiological and structural evidence for hippocampal involvement in persistent seizure susceptibility after traumatic brain injury. J Neurosci. 2001;21:8523–37.

    PubMed  CAS  Google Scholar 

  36. Zhang BL, Chen X, Tan T, Yang Z, Carlos D, Jiang RC, et al. Traumatic brain injury impairs synaptic plasticity in hippocampus in rats. Chin Med J (Engl). 2011;124:740–5.

    Google Scholar 

  37. Atkins CM, Truettner JS, Lotocki L, Sanchez-Molano J, Kang Y, Alonso OF, et al. Post-traumatic seizure susceptibility is attenuated by hypothermia therapy. Eur J Neurosci. 2010;28:35–42.

    Google Scholar 

  38. Lowenstein DH, Thomas MJ, Smith DH, McIntosh TK. Selective vulnerability of dentate hilar neurons following traumatic brain injury: a potential mechanistic link between head trauma and disorders of the hippocampus. J Neurosci. 1992;12:4846–53.

    PubMed  CAS  Google Scholar 

  39. Gao X, Deng-Bryant Y, Cho W, Carrico KM, Hall ED, Chen J. Selective death of newborn neurons in hippocampal dentate gyrus following moderate experimental traumatic brain injury. J Neurosci Res. 2008;86:2258–70.

    PubMed  CAS  Google Scholar 

  40. Sun D, Colello RJ, Daugherty WP, Kwon TH, McGinn MJ, Harvey HB, et al. Cell proliferation and neuronal differentiation in the dentate gyrus in juvenile and adult rats following traumatic brain injury. J Neurotrauma. 2005;22:95–105.

    PubMed  Google Scholar 

  41. Dash PK, Mach SA, Moore AN. Enhanced neurogenesis in the rodent hippocampus following traumatic brain injury. J Neurosci Res. 2001;63:313–9.

    PubMed  CAS  Google Scholar 

  42. Santhakumar V, Bender R, Frotscher M, Ross ST, Hollrigel GS, Toth Z, et al. Granule cell hyperexcitability in the early post-traumatic rat dentate gyrus: the 'irritable mossy cell' hypothesis. J Physiol. 2000;524(Pt 1):117–34.

    PubMed  CAS  Google Scholar 

  43. Kharatishvili I, Nissinen JP, McIntosh TK, Pitkanen A. A model of posttraumatic epilepsy induced by lateral fluid-percussion brain injury in rats. Neuroscience. 2006;140:685–97.

    PubMed  CAS  Google Scholar 

  44. Moser E, Moser MB, Andersen P. Spatial learning impairment parallels the magnitude of dorsal hippocampal lesions, but is hardly present following ventral lesions. J Neurosci. 1993;13:3916–25.

    PubMed  CAS  Google Scholar 

  45. Himanen L, Portin R, Isoniemi H, Helenius H, Kurki T, Tenovuo O. Longitudinal cognitive changes in traumatic brain injury: a 30-year follow-up study. Neurology. 2006;66:187–92.

    PubMed  CAS  Google Scholar 

  46. Andersen BB, Gundersen HJ, Pakkenberg B. Aging of the human cerebellum: a stereological study. J Comp Neurol. 2003;466:356–65.

    PubMed  Google Scholar 

  47. Woodruff-Pak DS, Foy MR, Akopian GG, Lee KH, Zach J, Nguyen KP, et al. Differential effects and rates of normal aging in cerebellum and hippocampus. Proc Natl Acad Sci U S A. 2010;107:1624–9.

    PubMed  CAS  Google Scholar 

  48. Keuker JI, Luiten PG, Fuchs E. Preservation of hippocampal neuron numbers in aged rhesus monkeys. Neurobiol Aging. 2003;24:157–65.

    PubMed  Google Scholar 

  49. Rapp PR, Gallagher M. Preserved neuron number in the hippocampus of aged rats with spatial learning deficits. Proc Natl Acad Sci U S A. 1996;93:9926–30.

    PubMed  CAS  Google Scholar 

  50. von Bohlen und Halbach O, Zacher C, Gass P, Unsicker K. Age-related alterations in hippocampal spines and deficiencies in spatial memory in mice. J Neurosci Res. 2006;83:525–31.

    Google Scholar 

  51. Mohajeri MH, Saini K, Li H, Crameri A, Lipp HP, Wolfer DP, et al. Intact spatial memory in mice with seizure-induced partial loss of hippocampal pyramidal neurons. Neurobiol Dis. 2003;12:174–81.

    PubMed  Google Scholar 

  52. Miyazaki S, Katayama Y, Lyeth BG, Jenkins LW, DeWitt DS, Goldberg SJ, et al. Enduring suppression of hippocampal long-term potentiation following traumatic brain injury in rat. Brain Res. 1992;585:335–9.

    PubMed  CAS  Google Scholar 

  53. Norris CM, Scheff SW. Recovery of afferent function and synaptic strength in hippocampal CA1 following traumatic brain injury. J Neurotrauma. 2009;26:2269–78.

    PubMed  Google Scholar 

  54. Zhang B, Chen X, Lin Y, Tan T, Yang Z, Dayao C, et al. Impairment of synaptic plasticity in hippocampus is exacerbated by methylprednisolone in a rat model of traumatic brain injury. Brain Res. 2011;1382:165–72.

    PubMed  CAS  Google Scholar 

  55. D'Ambrosio R, Maris DO, Grady MS, Winn HR, Janigro D. Selective loss of hippocampal long-term potentiation, but not depression, following fluid percussion injury. Brain Res. 1998;786:64–79.

    PubMed  Google Scholar 

  56. Reeves TM, Kao CQ, Phillips LL, Bullock MR, Povlishock JT. Presynaptic excitability changes following traumatic brain injury in the rat. J Neurosci Res. 2000;60:370–9.

    PubMed  CAS  Google Scholar 

  57. Reeves TM, Lyeth BG, Povlishock JT. Long-term potentiation deficits and excitability changes following traumatic brain injury. Exp Brain Res. 1995;106:248–56.

    PubMed  CAS  Google Scholar 

  58. Akasu T, Muraoka N, Hasuo H. Hyperexcitability of hippocampal CA1 neurons after fluid percussion injury of the rat cerebral cortex. Neurosci Lett. 2002;329:305–8.

    PubMed  CAS  Google Scholar 

  59. Reeves TM, Lyeth BG, Phillips LL, Hamm RJ, Povlishock JT. The effects of traumatic brain injury on inhibition in the hippocampus and dentate gyrus. Brain Res. 1997;757:119–32.

    PubMed  CAS  Google Scholar 

  60. Mtchedlishvili Z, Lepsveridze E, Xu H, Kharlamov EA, Lu B, Kelly KM. Increase of GABAA receptor-mediated tonic inhibition in dentate granule cells after traumatic brain injury. Neurobiol Dis. 2010;38:464–75.

    PubMed  CAS  Google Scholar 

  61. Santhakumar V, Ratzliff AD, Jeng J, Toth Z, Soltesz I. Long-term hyperexcitability in the hippocampus after experimental head trauma. Ann Neurol. 2001;50:708–17.

    PubMed  CAS  Google Scholar 

  62. Bonislawski DP, Schwarzbach EP, Cohen AS. Brain injury impairs dentate gyrus inhibitory efficacy. Neurobiol Dis. 2007;25:163–9.

    PubMed  CAS  Google Scholar 

  63. Hunt RF, Scheff SW, Smith BN. Regionally localized recurrent excitation in the dentate gyrus of a cortical contusion model of posttraumatic epilepsy. J Neurophysiol. 2010;103:1490–500.

    PubMed  Google Scholar 

  64. Hunt RF, Scheff SW, Smith BN. Synaptic reorganization of inhibitory hilar interneuron circuitry after traumatic brain injury in mice. J Neurosci. 2011;31:6880–90.

    PubMed  CAS  Google Scholar 

  65. Albensi BC, Sullivan PG, Thompson MB, Scheff SW, Mattson MP. Cyclosporin ameliorates traumatic brain-injury-induced alterations of hippocampal synaptic plasticity. Exp Neurol. 2000;162:385–9.

    PubMed  CAS  Google Scholar 

  66. Sick TJ, Perez-Pinzon MA, Feng ZZ. Impaired expression of long-term potentiation in hippocampal slices 4 and 48 h following mild fluid-percussion brain injury in vivo. Brain Res. 1998;785:287–92.

    PubMed  CAS  Google Scholar 

  67. Yaka R, Biegon A, Grigoriadis N, Simeonidou C, Grigoriadis S, Alexandrovich AG, et al. d-Cycloserine improves functional recovery and reinstates long-term potentiation (LTP) in a mouse model of closed head injury. FASEB J. 2007;21:2033–41.

    PubMed  CAS  Google Scholar 

  68. Schwarzbach E, Bonislawski DP, Xiong G, Cohen AS. Mechanisms underlying the inability to induce area CA1 LTP in the mouse after traumatic brain injury. Hippocampus. 2006;16:541–50.

    PubMed  CAS  Google Scholar 

  69. Hall ED, Bryant YD, Cho W, Sullivan PG. Evolution of post-traumatic neurodegeneration after controlled cortical impact traumatic brain injury in mice and rats as assessed by the de Olmos silver and fluorojade staining methods. J Neurotrauma. 2008;25:235–47.

    PubMed  Google Scholar 

  70. Tan SE, Liang KC. Spatial learning alters hippocampal calcium/calmodulin-dependent protein kinase II activity in rats. Brain Res. 1996;711:234–40.

    PubMed  CAS  Google Scholar 

  71. Atkins CM, Selcher JC, Petraitis JJ, Trzaskos JM, Sweatt JD. The MAPK cascade is required for mammalian associative learning. Nat Neurosci. 1998;1:602–9.

    PubMed  CAS  Google Scholar 

  72. Weeber EJ, Atkins CM, Selcher JC, Varga AW, Mirnikjoo B, Paylor R, et al. A role for the beta isoform of protein kinase C in fear conditioning. J Neurosci. 2000;20:5906–14.

    PubMed  CAS  Google Scholar 

  73. Kasahara J, Fukunaga K, Miyamoto E. Activation of calcium/calmodulin-dependent protein kinase IV in long term potentiation in the rat hippocampal CA1 region. J Biol Chem. 2001;276:24044–50.

    PubMed  CAS  Google Scholar 

  74. Kang H, Sun LD, Atkins CM, Soderling TR, Wilson MA, Tonegawa S. An important role of neural activity-dependent CaMKIV signaling in the consolidation of long-term memory. Cell. 2001;106:771–83.

    PubMed  CAS  Google Scholar 

  75. Jerusalinsky D, Quillfeldt JA, Walz R, Da Silva RC, Medina JH, Izquierdo I. Post-training intrahippocampal infusion of protein kinase C inhibitors causes amnesia in rats. Behav Neural Biol. 1994;61:107–9.

    PubMed  CAS  Google Scholar 

  76. Wolfman C, Fin C, Dias M, Bianchin M, Da Silva RC, Schmitz PK, et al. Intrahippocampal or intraamygdala infusion of KN62, a specific inhibitor of calcium/calmodulin-dependent protein kinase II, causes retrograde amnesia in the rat. Behav Neural Biol. 1994;61:203–5.

    PubMed  CAS  Google Scholar 

  77. Bourtchouladze R, Abel T, Berman N, Gordon R, Lapidus K, Kandel ER. Different training procedures recruit either one or two critical periods for contextual memory consolidation, each of which requires protein synthesis and PKA. Learn Mem. 1998;5:365–74.

    PubMed  CAS  Google Scholar 

  78. Satoh Y, Endo S, Ikeda T, Yamada K, Ito M, Kuroki M, et al. Extracellular signal-regulated kinase 2 (ERK2) knockdown mice show deficits in long-term memory; ERK2 has a specific function in learning and memory. J Neurosci. 2007;27:10765–76.

    PubMed  CAS  Google Scholar 

  79. Silva AJ, Paylor R, Wehner JM, Tonegawa S. Impaired spatial learning in alpha-calcium-calmodulin kinase II mutant mice. Science. 1992;257:206–11.

    PubMed  CAS  Google Scholar 

  80. Abeliovich A, Paylor R, Chen C, Kim JJ, Wehner JM, Tonegawa S. PKC gamma mutant mice exhibit mild deficits in spatial and contextual learning. Cell. 1993;75:1263–71.

    PubMed  CAS  Google Scholar 

  81. Abel T, Nguyen PV, Barad M, Deuel TA, Kandel ER, Bourtchouladze R. Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell. 1997;88:615–26.

    PubMed  CAS  Google Scholar 

  82. Kida S, Josselyn SA, de Ortiz SP, Kogan JH, Chevere I, Masushige S, et al. CREB required for the stability of new and reactivated fear memories. Nat Neurosci. 2002;5:348–55.

    PubMed  CAS  Google Scholar 

  83. Fineman I, Hovda DA, Smith M, Yoshino A, Becker DP. Concussive brain injury is associated with a prolonged accumulation of calcium: a 45Ca autoradiographic study. Brain Res. 1993;624:94–102.

    PubMed  CAS  Google Scholar 

  84. Hu B, Liu C, Bramlett H, Sick TJ, Alonso OF, Chen S, et al. Changes in trkB-ERK1/2-CREB/Elk-1 pathways in hippocampal mossy fiber organization after traumatic brain injury. J Cereb Blood Flow Metab. 2004;24:934–43.

    PubMed  CAS  Google Scholar 

  85. Yang K, Taft WC, Dixon CE, Todaro CA, Yu RK, Hayes RL. Alterations of protein kinase C in rat hippocampus following traumatic brain injury. J Neurotrauma. 1993;10:287–95.

    PubMed  CAS  Google Scholar 

  86. Folkerts MM, Parks EA, Dedman JR, Kaetzel MA, Lyeth BG, Berman RF. Phosphorylation of calcium calmodulin-dependent protein kinase II following lateral fluid percussion brain injury in rats. J Neurotrauma. 2007;24:638–50.

    PubMed  Google Scholar 

  87. Atkins CM, Chen S, Alonso OF, Dietrich WD, Hu BR. Activation of calcium/calmodulin-dependent protein kinases after traumatic brain injury. J Cereb Blood Flow Metab. 2006;26:1507–18.

    PubMed  CAS  Google Scholar 

  88. Atkins CM, Oliva Jr AA, Alonso OF, Chen S, Bramlett HM, Hu BR, et al. Hypothermia treatment potentiates ERK1/2 activation after traumatic brain injury. Eur J Neurosci. 2007;26:810–9.

    PubMed  Google Scholar 

  89. Dash PK, Mach SA, Moore AN. The role of extracellular signal-regulated kinase in cognitive and motor deficits following experimental traumatic brain injury. Neuroscience. 2002;114:755–67.

    PubMed  CAS  Google Scholar 

  90. Otani N, Nawashiro H, Fukui S, Nomura N, Shima K. Temporal and spatial profile of phosphorylated mitogen-activated protein kinase pathways after lateral fluid percussion injury in the cortex of the rat brain. J Neurotrauma. 2002;19:1587–96.

    PubMed  Google Scholar 

  91. Atkins CM, Oliva Jr AA, Alonso OF, Pearse DD, Bramlett HM, Dietrich WD. Modulation of the cAMP signaling pathway after traumatic brain injury. Exp Neurol. 2007;208:145–58.

    PubMed  CAS  Google Scholar 

  92. Hicks RR, Martin VB, Zhang L, Seroogy KB. Mild experimental brain injury differentially alters the expression of neurotrophin and neurotrophin receptor mRNAs in the hippocampus. Exp Neurol. 1999;160:469–78.

    PubMed  CAS  Google Scholar 

  93. Truettner J, Schmidt-Kastner R, Busto R, Alonso OF, Loor JY, Dietrich WD, et al. Expression of brain-derived neurotrophic factor, nerve growth factor, and heat shock protein HSP70 following fluid percussion brain injury in rats. J Neurotrauma. 1999;16:471–86.

    PubMed  CAS  Google Scholar 

  94. Griesbach GS, Gomez-Pinilla F, Hovda DA. The upregulation of plasticity-related proteins following TBI is disrupted with acute voluntary exercise. Brain Res. 2004;1016:154–62.

    PubMed  CAS  Google Scholar 

  95. Rosi S, Belarbi K, Ferguson RA, Fishman K, Obenaus A, Raber J, et al. Trauma-induced alterations in cognition and arc expression are reduced by previous exposure to (56)Fe irradiation. Hippocampus. 2010. doi:10.1002/hipo.20920.

  96. Chen S, Atkins CM, Liu CL, Alonso OF, Dietrich WD, Hu BR. Alterations in mammalian target of rapamycin signaling pathways after traumatic brain injury. J Cereb Blood Flow Metab. 2006;27:939–49.

    PubMed  Google Scholar 

  97. Schumann J, Alexandrovich GA, Biegon A, Yaka R. Inhibition of NR2B phosphorylation restores alterations in NMDA receptor expression and improves functional recovery following traumatic brain injury in mice. J Neurotrauma. 2008;25:945–57.

    PubMed  Google Scholar 

  98. Osteen CL, Giza CC, Hovda DA. Injury-induced alterations in N-methyl-d-aspartate receptor subunit composition contribute to prolonged 45calcium accumulation following lateral fluid percussion. Neuroscience. 2004;128:305–22.

    PubMed  CAS  Google Scholar 

  99. Kumar A, Zou L, Yuan X, Long Y, Yang K. N-Methyl-d-aspartate receptors: transient loss of NR1/NR2A/NR2B subunits after traumatic brain injury in a rodent model. J Neurosci Res. 2002;67:781–6.

    PubMed  CAS  Google Scholar 

  100. Biegon A, Fry PA, Paden CM, Alexandrovich A, Tsenter J, Shohami E. Dynamic changes in N-methyl-d-aspartate receptors after closed head injury in mice: implications for treatment of neurological and cognitive deficits. Proc Natl Acad Sci U S A. 2004;101:5117–22.

    PubMed  CAS  Google Scholar 

  101. Wakade C, Sukumari-Ramesh S, Laird MD, Dhandapani KM, Vender JR. Delayed reduction in hippocampal postsynaptic density protein-95 expression temporally correlates with cognitive dysfunction following controlled cortical impact in mice. J Neurosurg. 2010;113:1195–201.

    PubMed  CAS  Google Scholar 

  102. Campbell JN, Low B, Kurz JE, Patel SS, Young MT, Churn SB. Mechanisms of dendritic spine remodeling in a rat model of traumatic brain injury. J Neurotrauma. 2011;28:1–18.

    Google Scholar 

  103. Ansari MA, Roberts KN, Scheff SW. A time course of contusion-induced oxidative stress and synaptic proteins in cortex in a rat model of TBI. J Neurotrauma. 2008;25:513–26.

    PubMed  Google Scholar 

  104. Gong QZ, Phillips LL, Lyeth BG. Metabotropic glutamate receptor protein alterations after traumatic brain injury in rats. J Neurotrauma. 1999;16:893–902.

    PubMed  CAS  Google Scholar 

  105. Hoffmeister PG, Donat CK, Schuhmann MU, Voigt C, Walter B, Nieber K, et al. Traumatic brain injury elicits similar alterations in alpha7 nicotinic receptor density in two different experimental models. Neuromolecular Med. 2011;13:44–53.

    Google Scholar 

  106. Ciallella JR, Yan HQ, Ma X, Wolfson BM, Marion DW, DeKosky ST, et al. Chronic effects of traumatic brain injury on hippocampal vesicular acetylcholine transporter and M2 muscarinic receptor protein in rats. Exp Neurol. 1998;152:11–9.

    PubMed  CAS  Google Scholar 

  107. Wagner AK, Sokoloski JE, Ren D, Chen X, Khan AS, Zafonte RD, et al. Controlled cortical impact injury affects dopaminergic transmission in the rat striatum. J Neurochem. 2005;95:457–65.

    PubMed  CAS  Google Scholar 

  108. Dixon CE, Bao J, Johnson KM, Yang K, Whitson J, Clifton GL, et al. Basal and scopolamine-evoked release of hippocampal acetylcholine following traumatic brain injury in rats. Neurosci Lett. 1995;198:111–4.

    PubMed  CAS  Google Scholar 

  109. Prasad MR, Tzigaret CM, Smith D, Soares H, McIntosh TK. Decreased alpha 1-adrenergic receptors after experimental brain injury. J Neurotrauma. 1992;9:269–79.

    PubMed  CAS  Google Scholar 

  110. Sun DA, Deshpande LS, Sombati S, Baranova A, Wilson MS, Hamm RJ, et al. Traumatic brain injury causes a long-lasting calcium (Ca2+)-plateau of elevated intracellular Ca levels and altered Ca2+ homeostatic mechanisms in hippocampal neurons surviving brain injury. Eur J Neurosci. 2008;27:1659–72.

    PubMed  Google Scholar 

  111. Deshpande LS, Sun DA, Sombati S, Baranova A, Wilson MS, Attkisson E, et al. Alterations in neuronal calcium levels are associated with cognitive deficits after traumatic brain injury. Neurosci Lett. 2008;441:115–9.

    PubMed  CAS  Google Scholar 

  112. Kurz JE, Parsons JT, Rana A, Gibson CJ, Hamm RJ, Churn SB. A significant increase in both basal and maximal calcineurin activity following fluid percussion injury in the rat. J Neurotrauma. 2005;22:476–90.

    PubMed  Google Scholar 

  113. Warden DL, Gordon B, McAllister TW, Silver JM, Barth JT, Bruns J, et al. Guidelines for the pharmacologic treatment of neurobehavioral sequelae of traumatic brain injury. J Neurotrauma. 2006;23:1468–501.

    PubMed  Google Scholar 

  114. Whyte J, Vaccaro M, Grieb-Neff P, Hart T, Polansky M, Coslett HB. The effects of bromocriptine on attention deficits after traumatic brain injury: a placebo-controlled pilot study. Am J Phys Med Rehabil. 2008;87:85–99.

    PubMed  Google Scholar 

  115. Sawyer E, Mauro LS, Ohlinger MJ. Amantadine enhancement of arousal and cognition after traumatic brain injury. Ann Pharmacother. 2008;42:247–52.

    PubMed  CAS  Google Scholar 

  116. Whyte J, Hart T, Vaccaro M, Grieb-Neff P, Risser A, Polansky M, et al. Effects of methylphenidate on attention deficits after traumatic brain injury: a multidimensional, randomized, controlled trial. Am J Phys Med Rehabil. 2004;83:401–20.

    PubMed  Google Scholar 

  117. Hornstein A, Lennihan L, Seliger G, Lichtman S, Schroeder K. Amphetamine in recovery from brain injury. Brain Inj. 1996;10:145–8.

    PubMed  CAS  Google Scholar 

  118. Silver JM, Koumaras B, Chen M, Mirski D, Potkin SG, Reyes P, et al. Effects of rivastigmine on cognitive function in patients with traumatic brain injury. Neurology. 2006;67:748–55.

    PubMed  CAS  Google Scholar 

  119. Zhang L, Plotkin RC, Wang G, Sandel ME, Lee S. Cholinergic augmentation with donepezil enhances recovery in short-term memory and sustained attention after traumatic brain injury. Arch Phys Med Rehabil. 2004;85:1050–5.

    PubMed  Google Scholar 

  120. Morey CE, Cilo M, Berry J, Cusick C. The effect of Aricept in persons with persistent memory disorder following traumatic brain injury: a pilot study. Brain Inj. 2003;17:809–15.

    PubMed  Google Scholar 

  121. Albensi BC, Igoechi C, Janigro D, Ilkanich E. Why do many NMDA antagonists fail, while others are safe and effective at blocking excitotoxicity associated with dementia and acute injury? Am J Alzheimers Dis Other Demen. 2004;19:269–74.

    PubMed  Google Scholar 

  122. Marshall S, Teasell R, Bayona N, Lippert C, Chundamala J, Villamere J, et al. Motor impairment rehabilitation post acquired brain injury. Brain Inj. 2007;21:133–60.

    PubMed  Google Scholar 

  123. Cicerone KD, Dahlberg C, Malec JF, Langenbahn DM, Felicetti T, Kneipp S, et al. Evidence-based cognitive rehabilitation: updated review of the literature from 1998 through 2002. Arch Phys Med Rehabil. 2005;86:1681–92.

    PubMed  Google Scholar 

  124. Hamm RJ, Temple MD, O'Dell DM, Pike BR, Lyeth BG. Exposure to environmental complexity promotes recovery of cognitive function after traumatic brain injury. J Neurotrauma. 1996;13:41–7.

    PubMed  CAS  Google Scholar 

  125. Atkins CM, Falo MC, Alonso OF, Bramlett HM, Dietrich WD. Deficits in ERK and CREB activation in the hippocampus after traumatic brain injury. Neurosci Lett. 2009;459:52–6.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the National Institutes of Health: NS069721, AG033266 and NS056072 and the United States Army Medical Research and Materiel Command: PR054538.

Conflict of interest

The author declares no conflict of interest pertaining to this work.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Coleen M. Atkins.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Atkins, C.M. Decoding Hippocampal Signaling Deficits After Traumatic Brain Injury. Transl. Stroke Res. 2, 546–555 (2011). https://doi.org/10.1007/s12975-011-0123-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12975-011-0123-z

Keywords

Navigation