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C03 Transformation of CA1 pyramidal cells into pacemakers of epileptic network activity

Transient insults such as status epilepticus can convert normal brains to a chronically epileptic state, a process termed epileptogenesis. In this project, we will focus on a distinctive population of neurons with an acquired increased propensity for all-or-nothing intrinsic burst discharges present in hyperexcitable hippocampi in temporal lobe epilepsy (TLE). In previous work, we have discovered that the key mechanism in converting neurons to intrinisically bursting neurons is an upregulation of 

CaV3.2, a T-type Ca2+ channel subunit (ICaT). In this project, we will use techniques to genetically label these neurons, and analyze their role in synchronizing neuronal ensembles and initiating aberrant neuronal activity. In addition, we will implement silencing approaches using selective expression of “designer receptors exclusively activated by a designer drug” (DREADDs) or tetanus toxin light chain fragments (TnTX), in order to address the consequences of silencing CaV3.2-dependent bursting neurons. Using these strategies, we expect to obtain novel insights in the role of intrinsically bursting neurons as hubs of micronetwork discharges, and proof-of principle of the utility of inhibiting these cell types for control of epilepsy.