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

Many conditions leading to epilepsy are initially associated with a dysfunctional blood-brain barrier (BBB), resulting in alterations of the extracellular electrolytes, exsudation of serum proteins- including albumin- and vasogenic edema. We have recently shown that albumin activates a transforming growth factor beta (TGF beta-dependent signaling pathway, preferentially in astrocytes, leading to impaired astrocytic functions, followed by the development of neuronal hypersynchronization and seizures. Next, we propose to test the detailed changes in neuronal circuitry in response to hippocampal exposure to dysfunctional BBB, albumin or TGF-beta. We will use intraventricular perfusion (via implanted osmotic pumps) for varying periods of time. Consequent alterations in hippocampal properties and in EEG signals will be analyzed across the epileptogenic and the epileptic periods. Specifically, alterations in short-term and long-term synaptic plasticity and heterosynaptic plasticity, as well as alterations in synaptic connectivity, will be analyzed. Losartan and the ALK5 inhibitor SJN will be used to interfere with TGFß dependent signaling cascades and tested for effects on neurological outcome. These experiments will be complemented by studies in mice that lack TGFß receptors on astrocytes. This project will include both ex-vivo experimentation in slices and in-vivo monitoring and treatment, and will be supplemented by imaging analysis and immunhistology, in a tight collaboration between the Israeli and the German labs.

• DFG Programme: Research Grants
• International Connection: Israel
• Ehemaliger Antragsteller: Professor Dr. Uwe Heinemann, until 11/2016 (†)