Professor
In our lab we study basic cellular mechanisms of neuronal function in mammalian cortical structures. Our main focus is on mechanisms that underlie epilepsy, a common neurological disorder (0.5-1% world-wide), characterized by recurrent seizures. A seizure is a sudden interruption in normal brain function during which a large population of neurons fires repetitively and in high synchrony. A cortical structure having a low threshold for seizure generation is the hippocampus. Even when cut into thin slices and maintained in a dish in artificial physiological conditions, rat hippocampal tissue readily can be induced to generate seizure-like discharges. This provides us with an experimentally advantageous model for studying the cellular and molecular mechanisms of epilepsy.
Our scientific research focuses on the mechanisms controlling the intrinsic excitability of nerve cells (neurons) in the hippocampus – a brain structure implicated in learning and memory and in numerous neurological and neurodegenerative diseases. In particular, we study how the expression and function of membrane ion channels and ion pumps, which determine the firing properties of principal neurons, are altered in hippocampal neurons of epileptic animals.
In an experimental rat model of “acquired epilepsy” (chronic epilepsy secondary to a brain insult), we recently found that hippocampal pyramidal cells become intrinsically hyperexcitable. This alteration is due predominantly to a protein kinase A (PKA)-mediated of a ubiquitous class of potassium ion channels, KCa3.1, whose main function is to dampen neuronal excitability. Most importantly, this “acquired channelopathy” can be acutely reversed by PKA inhibitors, leading to recovery of function and normalization of neuronal excitability.
More recently we found in this model that the PKA signaling causing KCa3.1 downregulation is due to enhanced protein expression of corticotropin releasing factor (CRF) and of its type 1 receptor (CRF1R) in the hippocampus. Congruently, acute application of selective CRF1R antagonists restored KCa3.1 channel activity, thereby restoring KCa3.1 activity and normalizing intrinsic neuronal excitability. Moreover, we found that even a single injection of an CRF1R antagonist to chronically epileptic animals markedly decreases the frequency of electrographic seizures in all treated animals for several hours after treatment. We now attempt to translate these basic findings to novel antiepileptic therapies.
ISF
DFG
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