The overall goal of the Weston Lab's research program is to understand how the brain balances excitation and inhibition in cortical circuits so that it can generate proper pattens of network activity. To do this, the lab, led by Matthew Weston, Ph.D., studies gene variants that cause human childhood epilepsies and seeks to understand how they alter neuronal physiology to cause network hyperexcitability and seizures. These intractable epilepsies of childhood, collectively referred to as Developmental Epileptic Encephalopathies (DEEs), have devastating effects on patients and caregivers, making them a significant health problem. Studying this group of diseases provides a strong framework for the lab's goal of linking molecular and cellular changes to whole organism phenotypes. This is due to the fact that, on one end, DEEs have a strong genetic basis: almost half of patients that come to the clinic are given a genetic diagnosis, and there are up to 50 verified genes that cause DEEs. Together with its collaborators, the lab has been at the forefront of taking DEE-causing gene variants discovered in the clinic and creating mouse models with orthologous variants. This provides the team with a tractable model system that has a defined starting point for molecular pathology and a plethora of molecular genetic tools to employ. On the other end, the primary symptom of DEEs, epileptic seizures, are detectable and rigorously quantifiable in mice. We use electroencephalography (EEG) and in vivo Ca++ imaging to detect, localize, and characterize seizures and other, more subtle alterations in brain activity.
The gene variant and the seizures are the start and end points, respectively. To interrogate the mechanisms that link the two, the lab uses patch clamp electrophysiology to measure changes in membrane excitability and synaptic transmission, and multicellular Ca++ imaging to measure microcircuit activity. Importantly, Weston and his lab investigate both excitatory and inhibitory synaptic transmission and neuron subtypes, with the goal of identifying cell-type-specific mechanisms as targets to improve the treatment of the disease with fewer side effects.