Malformed cortex produces a spectrum of neurological deficits, from dyslexia and mild retardation to cerebral palsy, with epileptic seizure comorbid throughout this range. Epilepsies associated with developmental malformations are among the most difficult forms to treat with currently available anti-epileptic medications. The neonatal transcranial freeze lesion model mimics the histopathology and hyperexcitability typical of human acquired polymicrogyria. Recent studies show that cortical inhibitory interneuron subtypes are differentially altered in this malformed cortex. Translaminar, intracolumnar projecting inhibitory cells that show low-threshold spiking properties and contain somatostatin (SS) have an increased excitatory input and show an enhanced sensitivity to metabotropic glutamate receptor (mGluR) modulators in malformed cortex. While modulatory in control cortex, these neurons appear to be more powerful in malformed cortex, likely contributing to increased columnar synchrony that can then initiate the epileptiform activity. In addition, increased expression of mGluR5, critical to cortical development, occurs while the microgyral region is still forming, likely promoting aberrant connections. The goal of the current project is o determine whether modulating the activity of SS neurons and mGluR5 receptors can prevent and/or treat the epileptiform activity as well as cellular abnormalities associated with this developmental cortical malformation. Antagonists for mGluR5 are already in use clinically, making them likely viable candidates for human epilepsy patients. Optogenetic techniques will be combined with whole cell patch clamp and field potential recordings to determine whether selective manipulation of SS and other interneuron subtypes can control epileptiform activity (AIM1). To determine if blockade of mGluR5 or treatment with gabapentin reduce both epileptiform activity and cellular abnormalities (AIM2) with injections of the drugs given over a period of days. As a test of whether blocking the early increase in mGluR5 might prevent the development of epileptiform activity and pro-epileptogenic changes (AIM3), mGluR5 receptors will be focally blocked with slow-release methods over the area of malformation. Recordings will be made after the typical onset time of epileptiform activity to test whether this exposure can prevent onset. In addition, selective optical activation of either pyramidal neurons or specific inhibitory interneurons will allow for determination of which aspects of the circuitry can be altered with this treatment. These experiments will determine both whether mGluR antagonists are effective treatments and the cellular and network mechanisms affected. Relevance. Many epilepsy patients with developmental cortical malformations have intractable seizures. This work will determine whether a currently available medication would be effective for either prevention or treatment of epileptiform activity associated with these malformations.
This project seeks to identify novel targets for treatment of epilepsy associated with developmental brain malformations. These studies will determine both cellular and systems mechanisms that contribute specifically to the onset of epileptiform activity, with the ultimate goal of developing preventative therapies or reparative treatments for children with intractable seizures.
| Strack, Beata; Jacobs, Kimberle M; Cios, Krzysztof J (2014) Simulating vertical and horizontal inhibition with short-term dynamics in a multi-column multi-layer model of neocortex. Int J Neural Syst 24:1440002 |
| Bell, Andrew; Jacobs, Kimberle M (2014) Early susceptibility for epileptiform activity in malformed cortex. Epilepsy Res 108:241-50 |
| George, Amanda L; Jacobs, Kimberle M (2011) Altered intrinsic properties of neuronal subtypes in malformed epileptogenic cortex. Brain Res 1374:116-28 |
