Characterization of excitotoxicity induced transcriptional dysregulation

We describe the dysregulation of neuronal-activity dependent genes during the condition of toxic glutamate concentrations in primary hippocampal neurons. Genes differed in their response towards the loss of neuronal activity and the active shut-off of transcription. The most shut-off genes also show more direct synaptic function than the passively downregulated genes hinting to functional relevance of the shut-off mechanism. Findings were confirmed in an in vivo excitotoxicty model of Huntington´s disease. Five independent primary hippocampal preparations were treated with the GABAA receptor inhibitor bicuculline to induce transcription of synaptic-activity dependent genes. Following different durations of bicuculline treatment the active transcription shut-off was introduced by NMDA application and the passive shut-off by TTX application.