The overall goal of this project is to establish the time course for developing abnormalities in hippocampal
neural circuit action potential firing dynamics after pilocarpine induced hippocampal injury, determine whether
maintenance of normal neuronal firing dynamics prevents epileptogenesis and establish the genetic
mechanisms of those effects.
Temporal lobe epilepsy (TLE) associated with mesial temporal sclerosis (MTS) is a common form of focal
epilepsy in which seizures are difficult to treat and memory impairments are common. These factors
enormously diminish the quality of life of people with TLE. MTS/TLE develops after brain injury via
pathophysiological processes that take at least weeks to reach the endpoint of seizures and memory
impairments. This suggests that there is a window of therapeutic opportunity to minimize adverse outcomes.
Epileptogenesis is associated with an enormous number of pathological changes at the levels of gene
expression, inflammation, synaptic plasticity, neuronal loss and neuronal reorganization amongst many others.
Targeting individual pathogenic mechanisms has had limited success in preventing adverse outcomes in
animal models of TLE. Thus, new approaches to preventing epileptogenesis are required. We suggest that the
above pathophysiological processes converge to disrupt neural dynamics (the patterns of action potential firing
over time). The consequent abnormal activity dependent sculpting of synaptic weights and gene expression
iteratively alters the self-organization rules governing the formation of dynamic hippocampal circuits, with the
emergence of a maladapted circuit. Brain stimulation to maintain normal dynamics from forming thus
represents a novel approach to modifying epileptogenesis. The observation that brain stimulation can minimize
seizures and improve cognition outside of stimulation periods in animal models with structural brain
abnormalities, including MTS, supports the view that patterns of neural activity can be modified to improve
network function. It remains unknown whether stimulation during the process of epileptogenesis reduces the
development of maladaptive circuits. We will use optimized stimulation paradigms to perturb hippocampal firing
patterns during the post-injury period to maintain normal interictal dynamics and establish whether this
improves outcomes and whether gene expression changes provide mechanistic insight that could also be
harnessed for therapeutic gain.