|Position||Host institution||PhD enrolment||Start date||Duration|
|ESR11||P8-CU||Y (at CU)||early 2017||36 months|
Nature of the GABA transporter GAT1 malfunction in thalamic astrocytes in absence epilepsy
Increased tonic GABAA receptor inhibition in the thalamus is necessary and sufficient for induction of seizures of experimental absence epilepsy (AE). Drugs that increase GABA levels elicit and aggravate absence seizures (ASs) in normal individuals and in AE patients. Although tonic inhibition results from malfunction of the astroglial GABA transporter GAT1, there are no genetic abnormalities of the GAT1 gene. Here, it will be investigated in situ and in vivo whether thalamic GAT1 malfunction in genetic animal models of AE results from either 1) abnormal phosphorylation, 2) failure of trafficking to the outer astrocytic membrane, and/or 3) misplaced localization with respect to synaptic or extrasynaptic regions of the GABAergic synapses between thalamic reticular and thalamocortical neurons.
Experiments will involve 3H-GABA uptake, biotinylation experiments and live trafficking of fluorescence-tagged GAT1 in thalamic slices and in cultures of pure thalamic astrocytes) as well as immunogold EM localization of GAT1 transporter, GABAB and δ-subunit containing GABAA receptor and in thalamic regions. This work will be carried out in rat and mouse models of absence epilepsy.