Morphological changes among hippocampal dentate granule cells exposed to early kindling-epileptogenesis

Abstract

Temporal lobe epilepsy is associated with changes in the morphology of hippocampal dentate granule cells. These changes are evident in numerous models that are associated with substantial neuron loss and spontaneous recurrent seizures. By contrast, previous studies have shown that in the kindling model, it is possible to administer a limited number of stimulations sufficient to produce a lifelong enhanced sensitivity to stimulus evoked seizures without associated spontaneous seizures and minimal neuronal loss. Here we examined whether stimulation of the amygdala sufficient to evoke five convulsive seizures (class IV or greater on Racine’s scale) produce morphological changes similar to those observed in models of epilepsy associated with substantial cell loss. The morphology of GFP-expressing granule cells from Thy-1 GFP mice was examined either one day or one month after the last evoked seizure. Interestingly, significant reductions in dendritic spine density were evident one day after the last seizure, the magnitude of which had diminished by one month. Further, there was an increase in the thickness of the granule cell layer one day after the last evoked seizure, which was absent a month later. We also observed an increase in the area of the proximal axon, which again returned to control levels a month later. No differences in the number of basal dendrites were detected at either time point. These findings demonstrate that the early stages of kindling epileptogenesis produce transient changes in the granule cell body layer thickness, molecular layer spine density and axon proximal area, but do not produce striking rearrangements of granule cell structure.

Corneal kindled C57BL/6 mice exhibit saturated dentate gyrus long-term potentiation and associated memory deficits in the absence of overt neuron loss

“…In contrast, electrical kindling models also exhibit hippocampal-dependent memory impairment and neuronal hyperexcitability, but usually in the absence of overt hippocampal cell loss (see review (Hannesson and Corcoran, 2000)), which suggests more subtle changes in hippocampal physiology underlie these deficits (although there are exceptions to this rule: see (Cavazos et al, 1994; Cavazos and Sutula, 1990; Sutula, 1990)). Our results parallel the findings in electrical kindling models that report neuronal hyperexcitability, impaired long-term synaptic plasticity, and hippocampal-dependent spatial memory deficits in the absence of overt hippocampal damage (Brandt et al, 2004; Haas et al, 2001; Hannesson et al, 2001; Leung and Shen, 2006; Morimoto et al, 2004; Singh et al, 2013; Tooyama et al, 2002). However, it is noteworthy that these other electrical kindling models are constrained by the time- and labor-intensive nature of invasive implantation surgeries that cause a proinflammatory response in the brain.…”

“…However, the underlying pathological changes leading to memory dysfunction in these models can vary considerably depending on the age of the animal, the location of stimulation, and the extent of kindling (Hannesson and Corcoran, 2000; Morimoto et al, 2004). While some kindling studies employing direct electrical stimulation methods report minimal neuronal loss (Brandt et al, 2004; Haas et al, 2001; Singh et al, 2013; Tooyama et al, 2002), others report striking neuronal loss, sometimes resembling hippocampal sclerosis, after more extensive kindling protocols (Cavazos et al, 1994; Cavazos and Sutula, 1990; Chen et al, 2010; Sutula, 1990). Furthermore, all of these models suffer from the time- and labor-intensive nature of invasive electrode implantation surgeries and post-operative care.…”

Synaptopathies: synaptic dysfunction in neurological disorders – A review from students to students

“…; Isokawa ; Singh et al . ), and altered neurotransmitter receptor composition (Lopes et al . ; Zhou et al .…”

Hippocampal granule cell pathology in epilepsy — A possible structural basis for comorbidities of epilepsy?

“…2). Spine density changes are also evident among new cells during epileptogenesis, although the findings are complex: both spine density decreases [31–33] and increases [34, 35] have been observed. Interestingly, there appear to be critical periods during granule cell development when epileptogenic brain injuries can induce particular abnormalities.…”