Repair of the Injured Adult Hippocampus through Graft-Mediated Modulation of the Plasticity of the Dentate Gyrus in a Rat Model of Temporal Lobe Epilepsy

Abstract

Intracerebroventricular kainate administration in rat, a model of temporal lobe epilepsy (TLE), causes degeneration of the hippocampal CA3 pyramidal and dentate hilar neurons. This leads to a robust but aberrant sprouting of the granule cell axons (mossy fibers) into the dentate supragranular layer and the CA3 stratum oriens. Because this plasticity is linked to an increased seizure susceptibility in TLE, strategies that restrain the aberrant mossy fiber sprouting (MFS) are perceived to be important for preventing the TLE development after the hippocampal injury. We ascertained the efficacy of fetal hippocampal CA3 or CA1 cell grafting into the kainate-lesioned CA3 region of the adult rat hippocampus at early post-kainic acid injury for providing a lasting inhibition of the aberrant MFS. Analyses at 12 months after grafting revealed that host mossy fibers project vigorously into CA3 cell grafts but avoid CA1 cell grafts. Consequently, in animals receiving CA3 cell grafts, the extent of aberrant MFS was minimal, in comparison with the robust MFS observed in both "lesion-only" animals and animals receiving CA1 cell grafts. Analyses of the graft axon growth revealed strong graft efferent projections into the dentate supragranular layer with CA3 cell grafting but not with CA1 cell grafting. Thus, the formation of reciprocal circuitry between the dentate granule cells and the grafted CA3 pyramidal neurons is likely the basis of inhibition of the aberrant MFS by CA3 cell grafts. The results also underscore that grafting of cells capable of differentiating into CA3 pyramidal neurons is highly efficacious for a lasting inhibition of the abnormal mossy fiber circuitry development in the injured hippocampus.

Interneuron Progenitors Attenuate the Power of Acute Focal Ictal Discharges

“…Early approaches involved transplants of immortalized cortical neurons that reversibly overexpress GABA [6,39]. Transplants of these cells into the substantia nigra or dentate gyrus suppressed kindled hippocampal seizures [40]. Another promising approach involved the transplantation of embryonic stem cells engineered to produce adenosine [7,8].…”

Lentiviral RNAi-induced downregulation of adenosine kinase in human mesenchymal stem cell grafts: A novel perspective for seizure control

“…Thus, grafting of fetal hippocampal tissue with the aim to repair hippocampal networks in a kainic acid model of TLE led to partial reversal of hippocampal sclerosis (Rao et al, 2006;Shetty et al, 2005). Although cell transplantation approaches using fetal tissue or cells have yielded important basic results, stem cells have in recent years reached most attention and publicity as an alternative cell source for regenerative medicine.…”

Intranigral transplants of a GABAergic cell line produce long-term alleviation of established motor seizures

“…By inhibiting endogenous nigral cells, intranigral transplants of GABAergic cells could attenuate the inhibitory effect of the SNpr on anticonvulsant areas of the brain and could thus raise the seizure threshold, or block convulsive seizures [9,16]. These transplants would not be expected to restore the normal hippocampal circuitry as intrahippocampal CA3 fetal grafts appear to do [39], but to act more as a remote control system of epileptic seizures [9]. Some studies using intrahippocampal transplants of GABAergic cell lines have found positive effects in a model of kindling [42], but others have found no evidence for cessation of seizures or improvement in behavior using the KA model [22] RR352987891ES [37] have recently reported amelioration with fetal hippocampal grafts in the KA model.…”