Malformed cortex produces a spectrum of neurological deficits, from dyslexia and mild retardation to cerebral palsy, with epileptic seizures comorbid throughout this range. Epilepsies associated with developmental malformations are among the most difficult forms to treat with currently available anti-epileptic medications. Animal models specific to these types of epilepsies have been useful in identifying circuit abnormalities that contribute to hyperexcitability, including enhanced excitatory afferent input. Possible alterations in cortical inhibitory systems have been more controversial. Despite the presence of the altered excitatory circuits early in development, onset of epileptiform activity is delayed and does not occur in every case. This suggests that additional mechanisms are required for expression of the hyperexcitability. We hypothesize that differential changes in selective interneuron subgroups would potently enhance the expression of increased excitatory input. Specifically, we hypothesize that fast-spiking cells (FS) that normally prevent horizontal spread of excitatory activity are reduced in effectiveness, while low threshold-spiking cells (LTS) that effect vertical inhibition are enhanced in malformed cortex. The enhancement of vertical inhibition could produce hypersynchrony within a cortical column, thereby coordinating local excitatory activity and increasing the probability of spread. The reduction in FS cell effectiveness would further potentiate the spread of excitatory activity. The overall goal of these studies is to examine the role of inhibitory interneuron subtypes in normal and malformed, epileptogenic cortex. We propose the following three Specific Aims:
Aim 1 : To determine whether the synaptic input to FS and LTS cells is altered in the epileptogenic zone associated with cortical malformation.
Aim 2 : To isolate vertical (columnar) and horizontal cortical inhibitory output systems to determine if they are differentially affected in malformed cortex.
Aim 3 : To determine if there is a change in proportion or identity of interneuron subtypes in malformed cortex. We expect that these experiments will identify a new target for development of novel anti-epileptogenic treatments. 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.
|Bell, Andrew; Jacobs, Kimberle M (2014) Early susceptibility for epileptiform activity in malformed cortex. Epilepsy Res 108:241-50|
|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|
|George, Amanda L; Jacobs, Kimberle M (2011) Altered intrinsic properties of neuronal subtypes in malformed epileptogenic cortex. Brain Res 1374:116-28|