Stereological analysis of GluR2-immunoreactive hilar neurons in the pilocarpine model of temporal lobe epilepsy: Correlation of cell loss with mossy fiber sprouting

Abstract

Mossy fiber sprouting and the genesis of ectopic granule cells contribute to reverberating excitation in the dentate gyrus of epileptic brain. This study determined whether the extent of sprouting after status epilepticus in rats correlates with the seizure-induced degeneration of GluR2-immunoreactive (GluR2+) hilar neurons (presumptive mossy cells) and also quantitated granule cell-like GluR2-immunoreactive hilar neurons. Stereological cell counting indicated that GluR2+ neurons account for 57% of the total hilar neuron population. Prolonged pilocarpine-induced status epilepticus killed 95% of these cells. A smaller percentage of GluR2+ neurons (74%) was killed when status epilepticus was interrupted after 1-3.5 h with a single injection of phenobarbital, and the number of residual GluR2+ neurons varied among animals by a factor of 6.2. GluR2+ neurons were not necessarily more vulnerable than other hilar neurons. In rats administered phenobarbital, the extent of recurrent mossy fiber growth varied inversely and linearly with the number of GluR2+ hilar neurons that remained intact (P = 0.0001). Thus the loss of each GluR2+ neuron was associated with roughly the same amount of sprouting. These findings support the hypothesis that mossy fiber sprouting is driven largely by the degeneration of and/or loss of innervation from mossy cells. Granule cell-like GluR2-immunoreactive neurons were rarely encountered in the hilus of control rats, but increased 6-to 140-fold after status epilepticus. Their number did not correlate with the extent of hilar cell death or mossy fiber sprouting in the same animal. The morphology, number, and distribution of these neurons suggested that they were hilar ectopic granule cells.

Suppression of Adult Neurogenesis Increases the Acute Effects of Kainic Acid

“…Many newborn neurons become abnormal and could increase excitability rather than decrease it. For example, some GCs born in the days or weeks after SE migrate into the hilus instead of the granule cell layer and establish an aberrant ectopic population of granule cells (hilar ectopic granule cells or hEGCs; Parent et al, 1997; Scharfman et al, 2000; Jessberger et al, 2007; Jiao and Nadler, 2007; Yang et al, 2008; Fournier et al, 2010; Zhang et al, 2012; Koyama et al, 2012; Hester and Danzer, 2013) that creates a potential epileptic focus (Scharfman, 2004; Scharfman and Gray, 2009; Cameron et al, 2011; Pierce et al, 2011). HEGCs appear to have this pro-epileptic effect in the febrile seizure model also (Koyama et al, 2012).…”

Corruption of the dentate gyrus by “dominant” granule cells: Implications for dentate gyrus function in health and disease

“…One example is TLE following an insult or injury. In an animal model of this type of epilepsy, hEGC numbers, again based on stereological estimates, were up to 10x their normal number (McCloskey et al, 2006; Jiao & Nadler, 2007; Hester & Danzer, 2013). …”

Semilunar Granule Cells: Glutamatergic Neurons in the Rat Dentate Gyrus with Axon Collaterals in the Inner Molecular Layer

“…The dentate gyrus circuitry is reorganized in patients with this form of epilepsy because of sprouting of granule cell (GC) axons into the dentate IML (Houser et al, 1990). Although the initial trigger for the granule cell axon sprouting appears to be the loss of glutamatergic mossy cells that normally reside in the dentate hilus and project to the IML (Scharfman and Schwartzkroin, 1988;Jiao and Nadler, 2007), the functional consequences of dentate reorganization is controversial. Some studies using animal models of temporal lobe epilepsy suggest that sprouted granule cell axons selectively contact granule cell dendrites, increasing network excitability (Tauck and Nadler, 1985), whereas other studies find that sprouting GC axons function to enhance recurrent inhibition by increasing the excitatory drive to inhibitory interneurons (Sloviter, 1992).…”