Abstracts

Malformations of Cortical Development (MCD) are neurodevelopmental disorders characterized by cortical dyslamination, abnormal neuronal proliferation, dysplastic neurons, and altered cortical folding. Along with this, Patients with MCD typically present with cognitive impairments and are at an increased risk for depression and anxiety. One subtype of MCD, known as focal cortical dysplasia (FCD), presents with a single region of dyslamination in the cortex that causes irregular electrical activity resulting in epileptogenesis. MCDs like FCD are highly associated with genetic mutations in what is known as the mechanistic target of rapamycin pathway, or mTOR pathway. This pathway is a major regulator of transcription and translation and promotes cellular growth as well as regulates intracellular autophagy. Children with FCD have been found to also present with drug resistant epilepsy (DRE), meaning at least two anti-seizure medications have failed to produce lasting seizure freedom. Anti-seizure medications can be administered to offset the frequency and severity of epileptic seizures, however in cases of DRE, surgery is needed to remove the seizure focus. Of this population, roughly half will regain their recurrent seizures within 5 years of the operation.

I focused on answering the following in a mouse model of FCD: Do aberrantly migrating cells disrupt the lamination of adjacent cells? Does dyslamination affect the identity of the dyslaminated cells? Does mTOR upregulation in excitatory pyramidal cells change cortical inhibitory interneuron distribution? To accomplish this, I performed immunohistochemistry (IHC) on slices of mouse cortex at predetermined time points both embryonically and postnatally using cortical layer markers, then analyzed the quantity and density of neurons within those layers to determine neuronal migration patterns. I also reanalyzed previous data looking only at affected neurons to determine the layer-specific protein expression present in dyslaminated cells. Finally, I performed IHC on cortical interneurons and their surrounding peri-neuronal nets to analyze the quantity and migration patterns of interneurons in FCD regions.

I discovered that migration in adjacent cells and interneurons is normal at all ages through all layers, dyslaminated cells still express the marker for the layer they were destined for - they do not change expression to match the layer they end up in, there is a dramatic loss of interneurons in the cortex of mice with FCD, and epilepsy stemming from dyslamination, which is brought on by MCD, is responsible for a decrease in cortical interneurons.

I found that loss of inhibition in epileptic circuits may be caused by the recurrent seizures themselves, and not an underlying genetic factors within the subtype of epilepsy. This means excitatory/inhibitory imbalance in genetic epilepsy may be a result of DRE, rather than its cause. My project elaborated on previous findings to bring further insight into epileptogenesis and DRE in MCD.