In the Weston Lab, we use genetic mouse models of epilepsy that fall into two broad categories: (1) those that model mTORopathies, including loss-of-function Tsc1, Pten, and Szt2 mice, and (2) those that model genetic variants identified in human patients with intractable childhood epilepsies, including Kcnt1 gain-of-function, and Dnm1 and Iqsec2 loss-of-function, mice. We define and describe functional alterations in these genetic mouse models using a multilevel approach, ranging from whole-animal, in vivo techniques to single-neuron, in vitro techniques.

Detecting and Visualizing Epileptic Networks:

We monitor altered neuronal network activity in genetic mouse models of epilepsy using video-electroencephalogram (EEG), and widefield and multicellular calcium imaging (MCI), in awake, behaving mice. These approaches give us insight into the frequency and types of epileptic activity present in our genetic models (video-EEG), and help us to identify the cortical regions and spatial patterns (widefield), and the alterations in cellular activity (MCI), that underly the generation of epileptiform activity in the brain.

Model 1

 Research Image Credits: Erin Cullen and Willie Tobin

Identifying Synaptic Mechanisms of Epilepsy:

Dysfunction of neuronal membrane excitability and synaptic transmission is widely thought to be capable of generating the altered neuronal network activity that leads to seizures, epilepsy, and other neurodevelopmental disease phenotypes. Moreover, computational analysis of gene variants that cause epilepsy has shown that synaptic transmission is the biological process most likely to be affected by many of these variants. Thus, we perform in vitro and ex vivo electrophysiology, in dissociated neuron cultures and brain slices, to identify alterations in intrinsic neuronal membrane properties, and in synaptic transmission and connectivity, underlying epileptic activity.

Model 2
 Research Image Credits: Matt Weston and Amy Shore

Describing Morphological Alterations in Epileptic Models:

In addition to alterations in synaptic transmission, many epilepsies are characterized by alterations in brain architecture, especially those caused by gene variants that impact mTOR signaling. Thus, we use immunohistochemical techniques to assess alterations in individual neurons, such as the amount of synaptic input or the extent of dendritic branching, and in neuronal populations, such as the number and localization of neuronal subtypes in the cortex, from genetic mouse models of epilepsy.

Model 3 Research Image Credits: Amy Shore, Erin Cullen, and Matt Weston