|Position||Host institution||PhD enrolment||Start date||Duration|
|ESR8||P6-UKB||Y (at UKB)||early 2017||36 months|
Mechanisms underlying uncoupling of astrocytes in the epileptic brain
In human temporal lobe epilepsy (TLE), patients with hippocampal sclerosis (HS) show lack of gap junction coupling among astrocytes. In a TLE mouse model, unilateral intracortical kainate injection, morphological and functional changes reproduce those seen in chronic human HS. Importantly, uncoupling of astrocytes occurs already within 4 h after onset of status epilepticus (SE), thus preceding changes in neurons and generation of recurrent seizures (Bedner et al., 2015, Brain 138:1208). However, the mechanisms underlying SE-induced uncoupling are unclear.
We will use reporter mice for Cx43 expression (Cx43kiECFP), immunodetection with antibodies recognizing distinct Cx43 phosphorylation sites and mass spectrometry to find out whether reduced expression or post-translational modification of Cx43 account for decreased coupling in TLE. Preliminary data indicate a role for pro-inflammatory cytokines in SE-induced gap junction blockade. Using mice lacking the corresponding receptors (TLR4 KO, IL-R1 KO, TNF-R1 KO, IL-R1/TNF-R1 dKO) or applying receptor antagonists (LPS-RS, IL-1ra, XPro1595) the underlying mechanisms will be explored.