Selective loss of dentate hilar interneurons contributes to reduced synaptic inhibition of granule cells in an electrical stimulation‐based animal model of temporal lobe epilepsy

Abstract

Neuropeptide-containing hippocampal interneurons and dentate granule cell inhibition were investigated at different periods following electrical stimulation-induced, self-sustaining status epilepticus (SE) in rats. Immunohistochemistry for somatostatin (SOM), neuropeptide Y (NPY), parvalbumin (PV), cholecystokinin (CCK), and Fluoro-Jade B was performed on sections from hippocampus contralateral to the stimulated side and studied by confocal laser scanning microscopy. Compared to paired age-matched control animals, there were fewer SOM and NPY-immunoreactive (IR) interneurons in the hilus of the dentate gyrus in animals with epilepsy (40 -60 days after SE), and 1, 3, and 7 days following SE. In the hilus of animals that had recently undergone SE, some SOM-IR and NPY-IR interneurons also stained for Fluoro-Jade B. Furthermore, there was electron microscopic evidence of the degeneration of SOM-IR interneurons following SE. In contrast, the number of CCK and PV-IR basket cells in epileptic animals was similar to that in controls, although it was transiently diminished following SE; there was no evidence of degeneration of CCK or PV-IR interneurons. Patch-clamp recordings revealed a diminished frequency of inhibitory postsynaptic currents in dentate granule cells (DGCs) recorded from epileptic animals and animals that had recently undergone SE compared with controls. These results confirm the selective vulnerability of a particular subset of dentate hilar interneurons after prolonged SE. This loss may contribute to the reduced GABAergic synaptic inhibition of granule cells in epileptic animals. Indexing termssomatostatin; neuropeptide Y; colocalization; status epilepticus Temporal lobe epilepsy (TLE) is a common form of acquired medically refractory partial epilepsy. The pathogenesis of TLE has been investigated intensively by human studies and animal models, which have provided several explanations for the increased excitability of neurons in the epileptic hippocampus. These potential mechanisms include sprouting of new axon collaterals resulting in the formation of recurrent excitatory connections on granule cells, changes in the intrinsic excitability of neurons (McNamara, 1999), and the altered expression of neurotransmitter receptors, such as NMDA and GABA A receptors (Coulter, 2001 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptOne controversial and intensely investigated pathogenic mechanism is altered GABAmediated inhibition. Neuroanatomical studies in human surgical specimens and experimental animal models of TLE have demonstrated a loss of inhibitory interneurons in the hilus of the dentate gyrus of the hippocampus (de Lanerolle et al., 1989;Sloviter, 1991;Obenaus et al., 1993;Mathern et al., 1995;Houser and Esclapez, 1996;Kobayashi and Buckmaster, 2003). These neuroanatomical studies are supported by electrophysiological studies demonstrating diminished paired pulse inhibition of CA1 pyramidal neurons and dentate granule cells (DGCs) (Kapur et al., 1989;Lothman et al., 19...

Dysfunction of hippocampal interneurons in epilepsy

“…In addition, NPY increases in the hippocampus in KA-induced seizures, which suggests that the NPY-positive neurons are resistant to KA-induced seizures in the whole hippocampus, but NPY/NADPH-d-positive neurons have different sensitivities in its subregions [53] . This is contradictory to previous research [43,51] , and may be due to the different models and However, PV-positive interneurons are highly susceptible to acute seizure activity in both age groups [54] . Moreover, there are much greater decreases in the NPY-and PVpositive interneurons in the hippocampus of aged rats after seizures.…”

“…This is mainly because aging alone can substantially depletes these populations. 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] .…”

“…The loss and inhibition of NPY interneurons have been reported in the rapi d kindling and electrical stimulationinduced epilepsy models, respectively [43,51] . In addition, NPY increases in the hippocampus in KA-induced seizures, which suggests that the NPY-positive neurons are resistant to KA-induced seizures in the whole hippocampus, but NPY/NADPH-d-positive neurons have different sensitivities in its subregions [53] .…”

“…TLE is a common form of epilepsy. One of its pathogenic features is the loss of inhibitory interneurons, which can lead to decreased feed-forward inhibition, relatively increased excitatory circuit activity, alteration of synaptic structure, and reduced threshold and increased vulnerability of seizures [51,71] . SE exhibits seizure activity persisting for a sufficient length of time [72] .…”

Silencing Hyper-Excitable Neurons as a Treatment for Status Epilepticus and Temporal Lobe Epilepsy.

“…We found that scAAV5-GABRA4-TREK-M pre injected rats had significantly less fig 8F). However, no reduction was observed in FJC+ cells in the dentate gyrus, where neuronal death predominantly occurs in the hilus as others have observed previously (Wang, Ghosh et al 2008;Sun, Mtchedlishvili et al 2007). In order to quantify the number of dead cells which is represented by green colored FluoroJade -C stained neurons, we calculated the Fluoro-Jade C positive neurons in each brain slice.…”