Reversing CRF-induced inhibition of KCa3.1 channels to treat acquired epilepsy

• Applicant: Professor Dr. Heinz Beck
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 437921518

Epilepsy is one of the most common neurological disorders world-wide. Chronic epilepsy is characterized by brain hyperexcitability and the emergence of spontaneous seizures. A major fraction of epilepsy patients still exhibits seizures despite treatment with multiple AEDs, in particular in temporal lobe epilepsy (TLE). Furthermore, TLE is also associated with prominent cognitive comorbidities, ranging from memory deficits to mood disorders, for which there are currently no approved treatments available. Accordingly, there is great need for developing more effective drugs for both of these detrimental key symptoms of epilepsy. Our preliminary findings show that upregulation of the CRF-CRF1-PKA receptor signaling pathway causes down-regulation of KCa3.1 channel activity in experimental TLE. Thus, a key use-dependent mechanism inhibiting neuronal activity is lost. Importantly, we show that KCa3.1 channel activity can be recovered with CRF1 receptor antagonists, restoring neuronal excitability to a near normal level. Here we propose to further study this mechanism of brain hyperexcitability in TLE in order to establish its translational potential. We will further explore the mechanism and pharmacology of neuronal KCa3.1 down-regulation in experimental TLE and human hippocampal slices, and explore its reversibility using different clinically relevant CRF1 receptor antagonists. We will then use invasive long-term EEG monitoring in epileptic mice, to explore if spontaneous seizures can be suppressed via CRF1 receptor inhibition. We will subsequently test if restoring KCa3.1 via CRF1 receptor inhibition also improves cognition-related activity at cellular resolution in-vivo, using 2-photon calcium imaging techniques in experimental TLE. Finally, we will explore if CRF1 receptor antagonists improves learning and memory in kainate-SE epileptic mice. We expect that pursuing these objectives will provide fundamental insights on the role of KCa3.1 downregulation by CRF1 receptors in TLE, as well as on the possible clinical usage of CRF1 receptor antagonists as antiepileptics and cognitive enhancers in this epileptic disorder.

• DFG Programme: Research Grants
• International Connection: Israel
• International Co-Applicant: Professor Dr. Yoel Yaari