TP 5: Gehirnregion-abhängige Epileptogenese in einem konditionalen Mausmodell (kostenneutrale Laufzeitverlängerung)

30/09/2021 to 30/09/2026

P5 will study brain region‐ and time‐specific epileptogenesis in the conditional Scn1aA1783V mouse
model of Dravet syndrome (DS). Following results of the 1st funding period indicating regional
differences (hippocampus vs. cortical S1 region) of epileptogenic susceptibility for the generation of
specific seizure types (febrile and generalized tonic-clonic vs. absence-like seizures) in distinctly critical
time windows, Tasks 1/2 will now take advantage of newly available enhancers providing cell type28
FOR-2715-2 Epileptogenesis of genetic epilepsies – RU overview & coordination proposal
and region-specific genetic access to parvalbumin interneurons, a key cell population in DS. These tools
will be leveraged to further dissect the role of single network components of thalamo-cortical and
hippocampal loops (with expertise from P8) and address how neuronal alterations translate into circuit
dysfunction, generation of epileptic foci, ictogenesis and distinct seizure types. The work will include
in vitro patch clamping, 256-electrode multielectrode array recordings synchronized with Ca2+
widefield imaging, and in vivo video-EEG and 1-/2-photon Ca2+ imaging (with P6). In addition, P5 will
investigate Cacna1e ki mouse models newly generated in Z2 which carry GOF variants identified by P2
using slice electrophysiology and video-EEG recordings, and will study variants identified in projects
P1-P3 in neurons. P5 will test the therapeutic potential of specific channel blockers and ASOs in tsA201
cells, brain slices and in vivo together with P6.