cortex

Project number:

102

Project title:

Disturbances in potassium homeostasis and epileptogenesis

Project supervisor:

Prof. Dr. Uwe Heinemann

Project description:

One of the first events following lesions to the brain such as status epilepticus, trauma and ischemia is opening of the blood brain barrier and astrocytosis. We recently discovered that pharmacological blood brain barrier opening by bile salts lead to extravasation of albumin and a vasogenic edema which was partially controlled by uptake of albumine into astrocytes. This was rapidly leading to activation of astrocytes and subsequent down regulation of Kir channels. This was associated with alterations in potassium homeostasis leading to a reduced threshold for generation of spreading depression and later epileptogenesis. We would like to know :

1.Which signals lead to down regulation of potassium channels in astrocytes
2.Whether the down regulation of K channels leads to altered glutamate transport and altered glutamate and GABA synthesis and release
3.Whether apart from Kir channels also 2P channels are involved
4.Whether there is widening of the ES during and following extravasation of albumin
5.Whether similar changes occur in other models of brain disease and whether they are coupled to blood brain barrier opening.
6.How such changes can be clinically studied
7.Whether they can be prevented by drugs which prevent albumin uptake into astrocytes such as antagonists to TGF beta
8.Whether they can be prevented by drugs which tighten the blood brain barrier.

We will use electrophysiological methods including ion selective microelectrodes for these studies. Astrocytes will be identified by use of mice which express GFP under the GFAP promoter. Imaging studies will be used to determine uptake of proteins into astrocytes and other cells and to observe the signals associated with vasogenic edema in mice or rats Single cell RT PCR and chip technology wilol be used to study alterations in glial gene regulation with emphasis on glutamate and GABA metabolism.

Possible cortex partners for rotation:

Kai Kaila: Expert in dc recordings and ion homeostasis with particular emphasis on K transporters. Has an interesting model of febrile convulsions leading to later epilepsy
Eva Sykova She has wide experience in measuring properties of the ES and relating them to MRI signals