Seizure frequency correlates with loss of dentate gyrus GABAergic neurons in a mouse model of temporal lobe epilepsy
Each pathological abnormality listed above could be an epileptogenic mechanism. Loss of GABAergic interneurons would directly reduce inhibition of granule cells, the major excitatory neuron type of the dentate gyrus. Loss of mossy cells has been proposed to indirectly reduce inhibition of granule cells (Sloviter, 1987; Sloviter et al., 2003). In contrast, surviving mossy cells have been proposed to be pro‐epileptic by amplifying excessive activity of granule cells (Ratzliff, Santhakumar, Howard, & Soltesz, 2002; Santhakumar et al., 2000) and by bridging hyperactivity from burst‐firing CA3 pyramidal cells to granule cells (Scharfman, Smith, Goodman, & Sollas, 2001). Granule cell axon (mossy fiber) sprouting has been proposed to cause seizures by increasing recurrent excitation (Tauck & Nadler, 1985) and by indirectly reducing inhibition (Buhl, Otis, & Mody, 1996). Hilar ectopic granule cells have been proposed to be burst‐firing super‐connected hubs that can trigger seizures (Cameron, Zhan, & Nadler, 2011; Scharfman & Pierce, 2012). Astrogliosis has been proposed to be epileptogenic by multiple mechanisms (Binder & Steinhäuser, 2006; Gibbons, Smeal, Takahashi, Vargas, & Wilcox, 2013; Wetherington, Serrano, & Dingledine, 2008), including loss of cell domain organization (Oberheim et al., 2008), inflammation (Maroso et al., 2010), reduced inhibition (Ortinski et al., 2010), glutamate release (Clasadonte, Dong, Hines, & Haydon, 2013), disruption of adenosine homeostasis (Boison, 2016), and altered expression of chloride ion pumps (Robel & Sontheimer, 2016).
It is unclear if any of the pathological abnormalities in the dentate gyrus are epileptogenic. If a pathological abnormality were epileptogenic, then its severity might correlate with the frequency of spontaneous seizures. The underlying (and arguable) assumption is that if an abnormality causes seizures, then more of the abnormality would cause more seizures. If so, multiple mechanisms could be evaluated together in a single group of experimental subjects, revealing their relative importance. Hester and Danzer (2013) used this approach. They reported that the percentage of hilar ectopic granule cells, the amount of mossy fiber sprouting, and the extent of mossy cell loss all correlated with seizure frequency. The study, however, had limitations. Only nine epileptic mice were included, modern stereological methods were not used, and inhibitory interneurons were not evaluated.
In this study, seizure frequency and pathological abnormalities of the dentate gyrus were measured in an animal model of temporal lobe epilepsy. Pathological abnormalities were quantified using unbiased stereological techniques and tested for correlation with seizure frequency in 127 epileptic pilocarpine‐treated mice.