The Circadian Molecular Clock is a Biomarker for Epilepsy in Focal Cortical Dysplasia

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Abstract Focal epilepsy is the most common cause of epilepsy. The abnormal epileptogenic region of the brain that generates seizures or "seizure focus" is critically important because its removal often results in a complete cure of the epilepsy. However, this tissue is under studied. Our first transcriptome study demonstrated diminished expression of the CLOCK transcription factor in seizure focus in contrast to control tissue. In addition, the downstream targets of CLOCK, the PAR bZip transcriptions factors are also diminished in the seizure focus. The deletion of Par bZip transcription factors in mice causes epilepsy. Thus, the role of CLOCK in the seizure focus may be through its regulation of the Par bZip transcription factors. In our study of CLOCK, we find that the deletion of CLOCK changes synaptic numbers, especially in inhibitory synapses. However, the function of PAR bZip factors per se in synaptogenesis and synaptic maintenance has not been explored, despite reports of their roles in regulating neurotransmitter levels. Based on our published finding that increased neuronal hyperexcitability of CLOCK-deficient mutants is associated with changes in the number of inhibitory synaptic terminals on excitatory pyramidal neurons, we hypothesize that these changes are mediated by PAR bZip. The Aims of this Supplement will test the hypothesis that, as downstream effectors of CLOCK, PAR bZip transcription factors govern synaptic maintenance and stability (Aim 1), as well as the expression levels of synaptic proteins (Aim 2). Both Aims will utilize the triple PAR bZip knockout mouse, so that Sean will gain experience in histological techniques and advanced microscopy, as well as molecular analyses and bioinformatics.