Cole Nipper

Introduction. Temporal lobe epilepsy (TLE) is a disorder characterized by recurrent focal-onset seizures originating in the hippocampus. It is the most common form of refractory epilepsy, and it is estimated that over 150,000 individuals suffer from uncontrolled TLE in the United States.¹ A significant subset of refractory TLE patients have comorbidities or disease presentations that make them poor surgical candidates.² Without adequate treatment, the disease presents with progressive symptoms including increased seizure frequency, lower onset threshold, and neuro-psychiatric sequalae including depression.³ In order to develop novel therapies to address refractory TLE, there is a need for a better understanding of the mechanisms of epileptogenesis and disease progression at the cellular and network levels.⁴ Because researchers are unable to adequately study microscopic network activity empirically, a computational model of the dentate gyrus – hippocampal axis was utilized to elucidate the role of hilar ectopic granule cells in epileptogenesis and disease progression.^4,5 Methods. A static network model of the hippocampus and dentate gyrus was modified to replace five percent of granule cells with hyperactive cells. These ectopic cells exhibited the reduced inhibitory connectivity and decreased firing threshold observed previously in immunohistochemical and electrophysiological studies of hilar ectopic granule cells in BAX knock-out mice. These cells were arranged with other cellular constituents into ten lamellae in physiologically proportionate subpopulations. The cells were parameterized and connected according to their cell type. The firing rate of granule cells in the standard and modified models was tested by measuring firing distribution over a series of ten dissimilar inputs. The pattern separation ability of the model was tested by iterating ten pairs of inputs and measuring the relative cross correlation of paired outputs. Results. The ectopic granule cell model, despite the small number of hilar granule cells, demonstrated a marked six-fold reduction in pattern separation ability. The ectopic cells also demonstrated a twelve-fold higher firing rate at the expense of mature granule cell firing, which fired half as often.⁵ In other words, “dominant” pathways materialized from the altered network topology.⁵ Conclusion. These results revealed a mechanism by which TLE can worsen over time. Physiologic neuroplastic strengthening mechanisms may reinforce epileptiform “dominant” pathways at the expense of a normally distributed hippocampal network.⁵ Repeated physiologic insult may result in a cycle that reduces mossy fiber variance and lowers seizure threshold. For this reason, hilar ectopic granule cells should be considered a potential target in future therapies for refractory TLE.

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5. Scharfman HE, Myers CE. Corruption of the dentate gyrus by dominant granule cells: Implications for dentate gyrus function in health and disease. Neurobiol Learn Mem. 2016;129:69-82. doi:10.1016/j.nlm.2015.09.005.