Epilepsy, the hippocampus, and the cortex
Synchronous activity and high rates of activity in the mammalian brain are normal and necessary. Information from the cortex, the “conscious” anatomical level of the brain, is funneled through the hippocampus and other temporal lobe structures required for the formation of memories. Areas of cortex representing different modalities, such as visual processing and auditory processing, can communicate with each other synchronously across relatively great distances, binding these different modalities into perceptions. It seems that without the ability to synchronize cortical activity and form long-term associations between different cortical activities, we lose the abilities to form coherent perceptions and useful memories, respectively.
Unfortunately, the underlying architecture of this fantastic network provides a generous substrate for pathological seizures. Seizures have been compared to explosions or fires in the brain, and the symptoms of a seizure can range from merely the experience of an odd taste in the mouth to uncontrollable convulsions. Relatively small disruptions of the healthy synaptic architecture of the brain can lead to an epileptic disease state. Approximately 1% of the human population has some personal experience with epilepsy.
Our lab is currently pursuing research projects related to the understanding, prevention, and treatment of epilepsy. These include (1) understanding the role of STEP in modulating the survivability and responsiveness of vulnerable interneurons in the hippocampus (2) investigating the neuronal fate of stem cell derived neuronal precursors injected into the brains of epileptic mice (3) testing whether stem cell derived, GABAergic neurons can functionally integrate into hippocampal circuits and provide seizure-preventing inhibition. All of these projects are being pursued in collaboration with Prof. Jan Naegele, and projects (2) and (3) are also collaborations with Prof. Laura Grabel.
In addition, our lab is examining the dynamics of seizures that are functionally connected by the corpus callosum, the main white matter tract connecting the two cerebral cortices of the brain. Interestingly, an often useful treatment for otherwise intractable epilepsy is the cutting of the rostral part of the corpus callosum. Exactly why such a treatment is effective is not known, and we hope our research will supply some explanations.
We conduct this research mainly through the use of optical and electrophysiological methods of measuring neuronal activity. With fluorescent microscopy, we can measure calcium dynamics in several hundred neurons simultaneously. These calcium dynamics are indicative of action potential activity, and so we can measure the dynamics of circuit activity in hippocampal and neocortical tissue. We can also measure very small changes in membrane potential that occur in single neurons using whole-cell patch clamping, analyzing in fine detail the strength and kind of synaptic currents impinging on individual neurons. The latter technique also allows us to characterize a neuron’s spiking profile and morphology, both of which can help tell us what class of neuron we are examining. By studying the roles of individual neurons in the context of larger circuit dynamics, we are in a good position to unravel some of the mechanisms responsible for driving healthy neural circuits into epileptic regimes.