THE ROLE OF BLOOD-BRAIN BARRIER DYSFUNCTION AND ALBUMIN-INDUCED TGF-BETA SIGNALING IN NEURONAL PLASTICITY AND ASSOCIATED NETWROK MODIFICATIONS

• Applicant: Professor Dr. Dietmar Schmitz, since 1/2017
• Co-Applicant: Professor Dr. Alon Friedman
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 253162394

• Final Report Year: 2018

Final Report Abstract

Postinjury epilepsy (PIE) is a devastating sequela of various brain insults including traumatic brain injury and stroke. We previously reported TGF-β receptor mediated uptake of albumin in astrocytes after blood-brain barrier (BBB) dysfunction and prior to development of seizures. Under this project we investigated in detail the role of BBB dysfunction and TGF-β signaling in alterations in synaptic plasticity. We studied synaptic plasticity in hippocampal slices as these are well-characterized in the healthy hippocampus. In addition, BBB dysfunction is a feature of the peri-ischemic hippocampus. We reported significant changes in the pattern and extent of synaptic plasticity that favor hyperexcitability, at least partly explained by reduced inhibitory transmission, excitatory synaptogenesis and changes in the extracellular matrix. These changes were also associated with seizures in over two thirds of the rats. Hyperexcitability was similarly observed following intracerebroventricular administration of serum albumin. Albumin reduced long-term depression following low-frequency stimulation and increased long­term potentiation of population spikes in response to low-frequency (20 Hz) stimulation. These changes were reversible by blocking TGFβ receptor II (TGFβR-ll). While heterosynaptic plasticity was potentiated following albumin treatment, it was insensitive to TGFβ receptor II blockage. We also described, for the first time, that epileptogenesis under BBB dysfunction and TGFβ signaling is associated with persistent degradation of protective extracellular matrix (ECM) structures called perineuronal nets (PNNs), around fast-spiking inhibitory interneurons. We found similar changes in a rat model of TBI as well as in brains of human epileptic patients. Using the observed changes in network neuronal activity under BBB dysfunction, we explored the biomarker potential of various electrographic features to predict seizures in 5 post-injury epilepsy models. We found that dynamic changes in theta activity during epileptogenesis may serve as a promising diagnostic biomarker for epileptogenesis, and reliably predict the latency to the first spontaneous seizure. In addition to the primary workplan, we also studied mechanisms underlying seizure-induced cellular injury and report pericyte-mediated loss of capillary vasoreactivity as a potential cause of energy failure during seizures. To conclude, under this DFG project we continued the close and fruitful collaboration between the Berlin and Beer-Sheva laboratories. We extended the understanding of the mechanisms underlying BBB dysfunction-induced network modifications and associated increased neuronal excitability. We strongly believe that this project highlights novel targets for the diagnosis of epileptogenesis and prevention of post-injury epilepsy and associated co-morbidities.

Publications

• (2019) Seizure-induced microvascular injury is associated with impaired neurovascular coupling and blood-brain barrier dysfunction. Epilepsia 60 (2) 322–336
  Ofer Prager,Lyna Kamintsky,Luisa A. Hasam-Henderson,Karl Schoknecht,Vera Wuntke,Ismini Papageorgiou,Jutta Swolinsky,Valeria Muoio,Guy Bar-Klein,Udi Vazana,Uwe Heinemann,Alon Friedman,Richard Kovács
  
• Blood-brain barrier dysfunction can contribute to pharmacoresistance of seizures. Epilepsia. 2014 Aug;55(8):1255-63
  Salar S, Maslarova A, Lippmann K, Nichtweiss J, Weissberg I, Sheintuch L, Kunz WS, Shorer Z, Friedman A, Heinemann U
  
• Losartan prevents acquired epilepsy via TGF-β signaling suppression. Ann Neurol. 2014 Jun;75(6):864-75
  Bar-Klein G, Cacheaux LP, Kamintsky L, Prager O, Weissberg I, Schoknecht K, Cheng P, Kim SY, Wood L, Heinemann U, Käufer D, Friedman A
  
• Monitoring stroke progression: in vivo imaging of cortical perfusion, blood-brain barrier permeability and cellular damage in the rat photothrombosis model. J Cereb Blood Flow Metab 2014.34/11.1791-80
  Schoknecht K, Prager O, Vazana U, Kamintsky L. Harhausen D, Zille M, Figge L, Chassidim Y, Schellenberger E, Koväcs R, Heinemann U, Friedman A
  
• Albumin induces excitatory synaptogenesis through astrocytic TGF-β/ALK5 signaling in a model of acquired epilepsy following blood-brain barrier dysfunction. Neurobiol Dis. 2015 Jun;78:115-25
  Weissberg I, Wood L, Kamintsky L, Vazquez O, Mllikovsky DZ, Alexander A, Oppenheim H, Ardizzone C, Becker A, Frigerio F, Vezzani A, Buckwalter MS, Huguenard JR, Friedman A, Käufer D
  
• Synaptic plasticity in area CA1 of rat hippocampal slices following intraventricular application of albumin. Neurobiol Dis 2016; 91:155-65
  Salar S, Lapilover E, Muller J, Hollnagel JO, Lippmann K, Friedman A, Heinemann U
  
• Electrocorticographic dynamics as a novel biomarker in five models of epileptogenesis. J Neurosci 2017 Apr 26:37(17):4450-4461
  Milikovsky DZ, Weissberg I, Kamintsky L, Lippmann K, Schefenbauer O, Frigerio F, Rizzi M, Sheintuch L, Zelig D, Ofer J, Vezzani A, Friedman A
  
• Epileptiform activity and spreading depolarization in the blood-brain barrier-disrupted peri-infarct hippocampus are associated with impaired GABAergic inhibition and synaptic plasticity. J Cereb Blood Flow Metab 2017 May;37(5):1802-1819
  Lippmann K, Kamintsky L, Kim SY, Lublinsky S, Prager O, Nichtweiss JF, Salar S, Käufer D, Heinemann U, Friedman A
  
• Event-associated oxygen consumption rate increases ca. five-fold when interictal activity transforms into seizure-like events in vitro. Int J Mol Sci. 2017 Sep; 18(9):1825
  Schoknecht K, Bemdt N, Rosner J, Heinemann U, Dreier JP, Kovács R, Friedman A, Liotta A
  
• TGFβ signaling is associated with changes in inflammatory gene expression and perineuronal net degradation around inhibitory neurons following various neurological insults. Sci Rep 2017 Aug 9;7(1):7711
  Kim SY, Senatorov V, Morrissey CS, Lippmann K, Vazquez O, Milikovsky DZ, Gu F, Parada I, Prince DA, Becker AJ, Heinemann U, Friedman A, Käufer D