Identification of Zinc-sensitive Metal-regulatory Transcriptional Factor 1 Positive Neurons to Study Hippocampal Epileptic Network Activity

Annachiara Meconi¹, Susanne Schoch¹, Albert J. Becker¹, Karen M.J. van Loo¹

¹ Department of Neuropathology, University Medical Center Bonn

Temporal lobe epilepsy (TLE) is the most common focal seizure disorder in adults characterized by a hyperexcitable hippocampal network. It generally develops after a brain disease or an acute brain insult via underlying multistructural and functional neuronal alterations, referred to as epileptogenesis. Among these processes, acquired transcriptional channelophaties play a pivotal role. We recently discovered that after status epilepticus (SE), a rise in intracellular Zn²⁺ promotes Ca_v3.2 promoter activation via the zinc-sensible metal regulatory transcription factor-1 (MTF1). The transcriptional upregulation of Ca_v3.2 leads to an increased density of the T-type Ca²⁺-current (ICaT), an augmented propensity for burst discharges of hippocampal CA1 neurons as well as spontaneous seizures. Since little is known about MTF1-induced signaling cascades and their functional relevance in neuronal circuits, we developed a MTF1-transcriptional unit, consisting of a minimal promoter and five  metal responsive elements  (MREs-the transcriptional binding sites for MTF1-) in order  to genetically label MTF1-responsive cells. Currently we are using this transcriptional unit to analyse in detail the molecular and functional network recruited by Zn²⁺-sensitive MTF1-signaling in the hippocampal neuronal circuit.