Abstracts

Summary: The term "neurovascular unit" refers to the composite of the endothelium, extracellular matrix, astrocytes, pericytes and neurons. Recent studies from several laboratories indicate that proximal events in the endothelium trigger dysfunction of astrocytes and neurons. Such studies point to disturbed "blood-brain communication" as a critical causative factor in determining astrocytic functions and extracellular homeostasis, angiogenesis and inflammation - thus affecting neuronal excitability and network plasticity. In addition, excitability of the neuronal-astrocytic network determines the diameter of brain arterioles, which in turn may determine cerebral blood flow, vessels permeability and angiogenesis. In this workshop we will discuss recent studies dissecting the mechanisms underlying interactions within the neurovascular unit under healthy conditions and their potential role in epileptogenesis and epilepsy. Brian MacVicar (University of British Columbia) will discuss the role of astrocytic signaling in coupling changes in brain activity to regional alterations in cerebral blood flow. Using two-photon Ca2+ imaging and uncaging as well as intrinsic nicotinamide adenine dinucleotide (NADH) imaging of single cells as a measure of redox state, he shows that the ability of astrocytes to induce vasodilations over vasoconstrictions critically relies on the metabolic state of the tissue (or different states of brain activation). These data showing a key role for astrocytes in neurovascular coupling raise the issue of astrocytic (dis)functions in the epileptic tissue and their role in determining blood flow and neuronal excitability. Christian Steinhauser (University of Bonn) will discuss his recent findings in epilepsy patients suffering from hippocampal sclerosis, showing that astrocytes (Glu-T cells, displaying glutamate transporters and gap junctions) almost completely disappears while the remaining GluR-cells undergo alterations of their glutamate receptors, suggesting that glial cells may play a key role in the generation and/or spread of seizure activity. Mireille Lerner-Natoli (Institut de Génomique Fonctionnelle, Montpellier) will present data confirming pathological angiogenesis in the human intractable temporal lobe epilepsy and will discuss the role of seizures induce angiogenic processes in the generation of abnormal blood vessels lacking an intact blood-brain barrier (BBB). Daniela Kaufer (Berkeley, CA) will present experimental evidence confirming the role of BBB breakdown in the epileptogeneic process. She will present molecular and physiological data supporting the role of vascular damage, and specifically BBB breakdown in the induction of astrocytic transformation (mediated via serum albumin and transforming growth factor beta receptors), followed by inflammatory and neuronal signaling. The data presented in this investigator workshop based on animal and human studies challenge the common view of epileptogenesis, that neurons are the prime targets affected in this disease and propose novel targets for the prevention and treatment of epilepsy.