Servicenavigation

Project Details

Back

Projekt Print View

Altered functions of ion channels, membrane receptors and neuronal networks associated with thalamocortical dysrhythmia syndrome.

Subject Area Experimental and Theoretical Network Neuroscience
Molecular Biology and Physiology of Neurons and Glial Cells
Term from 2018 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 353966806
 
Final Report Year 2023

Final Report Abstract

Thalamic abnormalities are common in neurological and psychiatric diseases like depression, cocaine abuse and absence epilepsy. Based on the presence of slow delta and theta range bursting during wakefulness they are referred to as thalamocortical (TC) dysrhythmia syndromes (TCD). A hyperpolarized membrane potential of TC relay neurons is suggested to be part of the basis for aberrant burst activity. Beside the influence of GABAergic neurons, the functional interaction between mutually antagonistic membrane currents, especially the depolarizing hyperpolarization-activated and cyclic nucleotide-gated cation (HCN) and hyperpolarizing two pore domain K+ (K2P) channels are major constituents of neuronal membrane polarization and rhythmic burst activity in the TC system. Since altered properties of these channels are the basis for TCD-related aberrant activity, the analysis of their interplay and the effects of modulatory transmitters and compounds were major aims of the study. Our study revealed that functional TWIK-related K+ (TREK)-1 and voltage-activated K+ (Kv)7 channels limit neuronal activity in the TC system. The genetic loss of TREK-1 and the down regulation of Kv7.3 channels are associated with the occurrence of conditions of increased excitability. While TREK-1-deficient (TREK-1-/-) mice are characterized by the occurrence of sharp spindle waves in the reticular thalamic nucleus (NRT) that resemble epileptic spike-and-wave discharges (SWDs), mouse models of neuroinflammation and axonal demyelination are associated with a transient period of neuronal hyperexcitability and decreased Kv7 channel function. In addition, there is a positive correlation between the availability of thalamic HCN channels and neuronal excitability in the TC system. In a model of general axonal demyelination, a period of TC hyperexcitability is accompanied by increased thalamic HCN channel function. Therefore, K+ channel activators and HCN channel inhibitors may represent promising candidates to limit conditions of increased thalamocortical activity. In this respect, the selective HCN4 blocker, EC18, was characterized as an effective experimental tool and a potential lead compound. Novel TREK-1 activators were less effective in relay neurons. An important finding of the project was that demyelination has an anti-epileptic effect in a model of absence seizures, the C3H/HeJ mice. These results have very interesting implications since demyelinating strategies may interrupt the spread of generalized seizures, slow the progression of absence epilepsy and open up new avenues to further evaluation of the role of myelinating glia and other non-excitable cells in epilepsy.

Publications

 
 

Additional Information

© 2026 DFG Disclaimer / Copyright / Privacy Policy

Textvergrößerung und Kontrastanpassung