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The objective of the Marsh Lab is to identify the genetic, cellular, and network mechanisms of seizures and cognitive dysfunction in children. Toward this end, the lab has two primary research directions that are intricately related. One approach to develop an appreciation of the mechanisms that may lead to the early onset epilepsies is to develop models of known genetic etiologies.
The lab team currently studies transgenic mice with mutations in ARX, a protein that primarily controls how interneurons develop and is linked to families with an X-linked pattern of seizures, infantile spasms, and intellectual disability. The lab also performs studies on other mouse models, including those with mitochondrial mutations and IQSEC2 human mutations, and have worked with CDKL5 knockout, Sfn5a knock out, and other mouse models. In these models, the lab applies various cell biological, physiological, and behavioral techniques, including voltage-sensitive dye imaging, single cell physiology, MEA recordings and signal analysis to understand cellular and network changes in the developing brain that leads to epilepsy.
The second research direction involves a translational approach to determine the network and electrophysiological alterations in the brains of children with intractable, early-onset epilepsies. To do this the Marsh Lab has studied intracranial and scalp EEG from children with intractable focal epilepsies undergoing evaluation for epilepsy surgery as well as pre- and post-treatment. The lab has been extracting features from the EEG, primarily interictal spikes and sharps, and determining if they inform about network dynamics or can act as a biomarker for the ictal onset zone or of outcome of epilepsy surgery.
- Developmental time course of hippocampal dysfunction in the Arx mouse model
- Assessing CA1 hypoexctibability using in vivo single unit recordings in Arx
- Determining the role of cholinergic dysfunction in the Arx mouse model
- Pre-clinical study of novel cannabinoid for early onset seizures
- IQSEC2 mouse seizure characterization
- Cortico-cortical evoked potentials to map local and ictal networks across the age span
- Mapping spikes and local connectivity in human epileptic cortex
Dr. Marsh's research program focuses on understanding how changes in brain development lead to epilepsy, intellectual disability, and autism. He combines molecular and physiological tools in mouse models to ask questions about the interaction of normal development with single gene mutations to determine how the brain responds to perturbations in development.