PROJECT: JTC2009: EpiNet

As one of the most common neurological disorders (~8.000.000 patients in the EU), epilepsy has devastating behavioural, social and occupational consequences and is associated with accumulating brain damage and neurological deficits. The cardinal symptom of epilepsy is the occurrence of intermittent seizures, which on a cellular level consist of synchronized neuronal discharges. In epilepsy, progress has been made in identifying a large number of molecular and functional changes in different types of neurons. However, the complex nature of neuronal networks, with multiple constituent cell types and an intricate connectivity has hampered the development of a true understanding of the mechanisms underlying abnormal neuronal activity. As a consequence, the identification of causative changes in neuronal and network dynamics that underlie disease phenotypes has remained elusive. Novel light-based in-vitro and in-vivo stimulation and recording techniques, as well as novel electrophysiological techniques now allow addressing neuronal interactions on the level of elementary neuronal microcircuits, as well as on the level of larger neuronal ensembles. They also permit to assess the impact of specific neuronal ensembles on animal behaviour. We propose to apply these novel techniques to the study of epilepsy. We will focus on the role of altered inhibitory and excitatory microcircuits in controlling excitability and rhythmogenesis. Our specific goals are as follows: ? WP1: To reveal epilepsy-associated changes in dendritic processing of synaptic inputs in cortical principal neurons and how they are affected by GABAergic interneurons. ? WP2: To identify epilepsy-associated microcircuit reorganizations which are responsible for aberrant synchronization in cortical structures. ? WP3: To determine the impact of these altered cellular and circuit properties in the intact brain and to further develop in-vivo applications. These scientific goals will be achieved by conjointly using and further developing a number of emerging techniques in neuroscience research within the consortium. These are i) multiphoton uncaging and imaging, ii) in-vitro and in-vivo optogenetic stimulation, iii) retrovirus-based circuit mapping, iv) multi-electrode and optical population recording, and v) in-vivo multi-unit and intracellular recording techniques. The participating groups have a highly complementary expertise that allows us to combine these novel approaches to study the cellular and network changes in epilepsy. This approach will also provide a novel conceptual framework for the study of neuronal synchrony that can be applied to the analysis of other neurodegenerative brain disorders.