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C1: Experimentally induced granule cell dispersion as a model of pathological neuronal network dynamics

Carola HaasP, Ulrich EgertR and Michael FrotscherH,O


P = Experimental Epilepsy, University Medical Center;
H = Anatomical Institute
O = Center for Neuroscience,
R = Biomicrotechnology


Scientific background

Human temporal lobe epilepsy (TLE) is often accompanied by sclerosis in the hippocampus (HC) with neuronal degeneration and dentate gyrus granule cell (GC) dispersion. In spite of its clinical importance the functional properties of these changes are not well understood. A new mouse model of TLE with epileptiform electrical activity in the HC and GC dispersion, the signature of sclerosis, enables investigations connecting structural changes and pathophysiological activity dynamics.
In this network, mossy fiber sprouting and recurrent innervation of GCs suggest a feedback loop promoting synchronization of spike activity, possibly associated with a deteriorating inhibitory network. The field potentials dynamics evoked by electrical stimulation in HC slices of epileptic mice is abnormal. The strength of inhibitory synapses is, however, increased. How these changes of the HC microcircuitry and of the connected tissues contribute to epileptic activity is, however, still unclear.


Objectives

  • In the GC, reduced expression of reelin (a glycoprotein essential for layer formation in the brain) in TLE patients indicates its involvement in GC migration defects. GC dispersion in TLE is accompanied by reelin deficiency. Migration defects of GCs in reeler mice and mice without reelin receptors are associated with changes of the radial glial scaffold, the site of reelin signalling. We aim to understand the mechanisms leading to TLE and Ammon's horn sclerosis by investigating the consequences of GC dispersion on network activity and to understand the relation of structural changes and pathophysiological dynamics in TLE. We will study the mechanisms leading to a decreased reelin expression associated with GC dispersion and to potential abnormalities of the radial glial scaffold in these animals.

  • In the electrophysiological part of this project we aim to understand the mechanisms leading to TLE by investigating the consequences of HC sclerosis on network activity. What is the relation between structural changes and pathophysiological dynamics in TLE? Substrate integrated microelectrode arrays (MEAs) are used to analyze epileptiform activity in acute hippocampal slices. In in-vivo recordings epileptiform activity is analyzed to predict and detect seizures and behavioral changes, which may help to develop techniques to stop seizures early on. These experimental studies will be matched by simulated HC-like neuronal networks to investigate the network structure and mechanisms critical to elicit a seizure. While previous reports focused solely on the propagation of epileptic spikes, we identified network properties important for the dynamics in the initiation phase of such spikes.


The project closely interacts with related work in the BCCN projects A2, C2 and C3.

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