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XI European Meeting on Glial Cell Function in Health and Disease

Overview Session Overview Sessionprint print  
 

July 3, 2013 - Room 2 3:15pm - 5:15pm
Symposium 1: Glial Cells in Epilepsy: Novel Aspects and on Pathogenesis and Treatment

Organizers:
Alsa Pitkänen (Kuopio)
Rebecca Matsas (Athens)

3:15pm
S01-01

Bridging the gap between glial dysfunction and the seizing patient – a translational approach

*Kjell Heuser 1 , Karolina Szokol 1 , Erlend Nagelhus 2 , Erik Taubøll 1
1 Oslo University Hospital, , Oslo, Norway
2 University of Oslo, Institute of Basic Medical Sciences, Oslo, Norway
Abstract text :

Epilepsy comprises a range of different brain disorders, syndromes and conditions characterised by spontaneous recurrent seizures, and affects almost 1 % of the global population. Epilepsy interferes with the normal activities of daily living, employment status, social relationships, and is a significant risk factor for depression, injury, and death.
Pharmacological treatment is successful for the majority of epilepsy patients. However, still a large proportion of patients have little or no benefit from currently available antiepileptic drugs, which all are designed to have an effect on neurons. A condition frequently associated with pharmacoresistance is Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis (MTLE-HS). A hallmark of MTLE-HS is the proliferation and alteration of glial cells in the hippocampus and adjacent tissue. On the molecular level altered expression patterns of the astrocyte water channel aquaporin-4, the inwardly rectifying potassium channel Kir4.1 and dystrophin-associated protein complex (DAPC) have been found in the sclerotic hippocampus. Genetic studies have provided evidence for an association between altered Kir4.1 and epilepsy. A crucial question is in how far these glial changes contribute to generation and spread of seizures. As MTLE-HS often has a progressive course, is there any evidence for glial changes over time, and is there a therapeutic time window for prevention? A translational view is advantageous to solve these questions and to select appropriate candidates for therapeutic approaches.



3:45pm
S01-02

Neural stem cell transplantation in experimental temporal lobe epilepsy

*Rebecca Matsas 1
1 Hellenic Pasteur Institute, , Athens, Greece
Abstract text :

Epilepsy is a major neurological disease that affects 50 million people worldwide, thus representing a major health and economic burden to society. As nearly 30% of epileptic patients do not respond to existing medications, there is great need for new therapeutic modalities. Temporal lobe epilepsy (TLE) seen in approximately one third of epileptic patients, is typically characterized by partial seizures and hippocampal degeneration and is associated with learning and memory impairments. TLE is among the types of epilepsy which are often drug resistant and therefore is being considered as a possible clinical target for alternative stem cell-based therapies. Since insulin-like growth factor I (IGF-I) is neuroprotective following a number of experimental insults to the nervous system, we investigated the therapeutic potential of neural stem/progenitor cells (NSCs) transduced, or not, with a lentiviral vector for overexpression of IGF-I after transplantation in a mouse model of kainic acid (KA)-induced TLE. Exposure of mice to the Morris Water Maze task revealed that unilateral intrahippocampal NSC transplantation significantly prevented the KA-induced cognitive decline. Moreover, NSC grafting protected against neurodegeneration, reduced astrogliosis, and maintained endogenous neurogenesis at normal levels. In some cases, the beneficial effects of transplanted NSCs were manifested earlier and were more pronounced when these were transduced to express IGF-I. However, differences became less pronounced by 2 months post-grafting, since similar amounts of IGF-I were detected in the hippocampi of both groups of mice that received cell transplants. Grafted NSCs survived, migrated and differentiated into neurons - including glutamatergic cells - and not glia, in the host hippocampus. Our results demonstrate that transplantation of IGF-I producing NSCs is neuroprotective and restores cognitive function following KA-induced TLE.


Supported by EU FP7 264083 Neurosign, the Foundation BNP Paribas and the Greek General Secretariat for Research and Technology GRANTS 2272 ARISTEIA/ 09SYN-21-969.



4:15pm
S01-03

Novel treatment targets to combat epilepsy

*Asla Pitkänen 1
1 University of Eastern Finland, , Kuopio, Finland
Abstract text :

Brain insults like traumatic brain injury (TBI) or status epilepticus (SE) cause a myriad of changes in neuronal networks including neurodegeneration, axonal/myelin injury, microgliosis, astrogliosis, blood-brain-barrier damage, neurogenesis, and changes in extracellular matrix, which trigger epileptogenesis and eventually lead to the development of ictogenic network and appearance of unprovoked epileptic seizures. Due to complexity of the process, prevention of epileptogenesis after brain injury has remained as an unmet medical challenge. The successful strategy to realistically and in a cost-effective way to combat epileptogenesis in clinic has been envisioned to require (i) identification of novel targets and/or their combinations, (ii) identification of biomarkers that can be used to diagnose epileptogenesis, stratify patients-at-risk for antiepileptogenesis studies, and predict therapy response. Recent molecular profiling studies have provided an insight into molecular changes that contribute to formation of ictogenic neuronal networks, including genes regulating synaptic, neuronal or glial cell plasticity, cell death, proliferation, and inflammatory or immune response. In parallel, several plasma and imaging biomarkers probing these changes, particularly after TBI, have been identified. This presentation reviews these studies, particularly those assessing the potential of targeting glial cells or monitoring their activity as a biomarker in combat against epileptogenesis after brain injury.



4:45pm
S01-04

Astrocyte dysfunction in temporal lobe epilepsy.

*Christian Steinhaeuser 1 , Alexander Dupper 1 , Peter  Bedner 1
1 University of Bonn, , Bonn, Germany
Abstract text :

Glial cells are now recognized as active communication partners in the CNS, and this new perspective has rekindled the question of their role in pathology. We observe unusual immunohistochemical and functional phenotypes of glial cells surviving in the sclerotic hippocampus (HS) of patients mesial with temporal lobe epilepsy (MTLE), including a complete loss of gap junction coupling. It is, however, unclear whether these changes reflect the cause, effect or adaptive response in the progression of epilepsy. To gain insight into the temporal relationship between seizure development and astroglial uncoupling we have established a mouse model of MTLE (unilateral intracortical kainate injection) which reflects many key aspects of human MTLE. Changes in interastrocytic coupling were assessed by tracer diffusion studies in acute slices from mice at different time points post status epilepticus. These studies revealed a pronounced reduction of coupling already during the latent period (i.e. before onset of neuronal death and hyperactivity) and a complete loss of coupling during the early chronic phase, providing strong evidence that this dysfunction is a crucial factor in epileptogenesis. To evaluate the mechanism underlying the loss of astrocytic coupling in the sclerotic hippocampus we performed coupling analysis in toll-like receptor 4 knockout (TLR-4 KO) mice one day post SE. In these mice no seizure-induced reduction of coupling could be found, indicating that inflammatory molecules are the upstream signals responsible for this dysfunction. Indeed, induction of inflammation by LPS injection as well as incubation of acute slices with inflammatory cytokines resulted in a comparable inhibition of astrocytic communication. Using Cre-lox fate mapping for permanent labelling of astrocytes, we gained further support for the notion that astrocytes in HS do not transdifferentiate into another cell type but acquire another functional phenotype. Together, these data challenge the common view of epileptogenesis according to which changes in neurons are considered the prime cause of this condition.


 


Supported by Deutsche Forschungsgemeinschaft (SFB/TR3) and the European Commission (FP7-202167 NeuroGLIA)