“Dormant basket cell” hypothesis revisited: Relative vulnerabilities of dentate gyrus mossy cells and inhibitory interneurons after hippocampal status epilepticus in the rat

Abstract

The "dormant basket cell" hypothesis suggests that postinjury hippocampal network hyperexcitability results from the loss of vulnerable neurons that normally excite insult-resistant inhibitory basket cells. We have reexamined the experimental basis of this hypothesis in light of reports that excitatory hilar mossy cells are not consistently vulnerable and inhibitory basket cells are not consistently seizure resistant. Prolonged afferent stimulation that reliably evoked granule cell discharges always produced extensive hilar neuron degeneration and immediate granule cell disinhibition. Conversely, kainic acid-induced status epilepticus in chronically implanted animals produced similarly extensive hilar cell loss and immediate granule cell disinhibition, but only when granule cells discharged continuously during status epilepticus. In both preparations, electron microscopy revealed degeneration of presynaptic terminals forming asymmetrical synapses in the mossy cell target zone, including some terminating on gamma-aminobutyric acid-immunoreactive elements, but no evidence of axosomatic or axoaxonic degeneration in the adjacent granule cell layer. Although parvalbumin immunocytochemistry and in situ hybridization revealed decreased staining, this apparently was due to altered parvalbumin expression rather than basket cell death, because substance P receptor-positive interneurons, some of which contained residual parvalbumin immunoreactivity, survived. These results confirm the inherent vulnerability of dendritically projecting hilar mossy cells and interneurons and the relative resistance of dentate inhibitory basket and chandelier cells that target granule cell somata. The variability of hippocampal cell loss after status epilepticus suggests that altered hippocampal structure and function cannot be assumed to cause the spontaneous seizures that develop in these animals and highlights the importance of confirming hippocampal pathology and pathophysiology in vivo in each case.

Dysfunction of hippocampal interneurons in epilepsy

“…In addition, NPY-IR interneurons are evidently lost in the hilus of the dentate gyrus but preserved in the granule cell layer in electrical stimulation-induced epilepsy [51] . Similar losses of NPY-IR interneurons have been reported in KA models [55] .…”

“…SE exhibits seizure activity persisting for a sufficient length of time [72] . SE leads to the loss and structural reorganization of interneurons and weake ned excitatory inputs to inhibitory interneurons [55,73] . In other types of epilepsy, including complex partial epilepsy, myoclonic epilepsy, and generalized tonic clonic seizures, interneurons exhibit similar characteristics.…”

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

“…Such a mechanism has been reported in the hippocampus and EC layers II/III (Bekenstein and Lothman, 1993;Williams et al, 1993;Sloviter, 1987;Doherty and Dingledine, 2001;Sloviter et al, 2003;Kumar and Buckmaster, 2006). Experiments performed in pilocarpine-treated rats have also demonstrated that pharmacologically isolated, GABA A receptor-mediated IPSPs have more positive reversal potentials in neurons recorded in vitro from the epileptic subiculum, peirhinal cortex and amygdala (de Guzman et al, 2006;Benini and Avoli, 2005;Benini et al, 2011); these data often correlated with reduced levels of mRNA expression and immunoreactivity of the neuron-specific cotransporter KCC2.…”

Changes in neuropeptide Y protein expression following photothrombotic brain infarction and epileptogenesis

“…Numerous studies indicate that the dentate gyrus is frequently involved in the generation of epileptic seizures (Heinemann et al, 1992;Lothman et al, 1992) and may exhibit characteristic histochemical and histopathologic changes, including changes in NPY expression (Sloviter, 1983(Sloviter, , 1991Sloviter et al, 2003). NPY expression was found markedly increased in hilar GABAergic interneurons, granule cells and sprouted mossy fibers (Bellmann et al, 1991;Chafetz et al, 1995;Lurton and Cavalheiro, 1997;Scharfman et al, 1999Scharfman et al, , 2002Sperk et al, 1992;Takahashi et al, 2000;Vezzani et al, 1996).…”