Restoration of calbindin after fetal hippocampal CA3 cell grafting into the injured hippocampus in a rat model of temporal lobe epilepsy

Abstract

Degeneration of the CA3 pyramidal and dentate hilar neurons in the adult rat hippocampus after an intracerebroventricular kainic acid (KA) administration, a model of temporal lobe epilepsy, leads to permanent loss of the calcium binding protein calbindin in major fractions of dentate granule cells and CA1 pyramidal neurons. We hypothesize that the enduring loss of calbindin in the dentate gyrus and the CA1 subfield after CA3-lesion is due to disruption of the hippocampal circuitry leading to hyperexcitability in these regions; therefore, specific cell grafts that are capable of both reconstructing the disrupted circuitry and suppressing hyper-excitability in the injured hippocampus can restore calbindin. We compared the effects of fetal CA3 or CA1 cell grafting into the injured CA3 region of adult rats at 45 days after KA-induced injury on the hippocampal calbindin. The calbindin immunoreactivity in the dentate granule cells and the CA1 pyramidal neurons of grafted animals was evaluated at 6 months after injury (i.e. at 4.5 months post-grafting). Compared with the intact hippocampus, the calbindin in "lesion-only" hippocampus was dramatically reduced at 6 months post-lesion. However, calbindin expression was restored in the lesioned hippocampus receiving CA3 cell grafts. In contrast, in the lesioned hippocampus receiving CA1 cell grafts, calbindin expression remained less than the intact hippocampus. Thus, specific cell grafting restores the injury-induced loss of calbindin in the adult hippocampus, likely via restitution of the disrupted circuitry. Since loss of calbindin after hippocampal injury is linked to hyperexcitability, re-expression of calbindin in both dentate gyrus and CA1 subfield following CA3 cell grafting may suggest that specific cell grafting is efficacious for ameliorating injury-induced hyperexcitability in the adult hippocampus. However, electrophysiological studies of KA-lesioned hippocampus receiving CA3 cell grafts are required in future to validate this possibility.

Dysfunction of hippocampal interneurons in epilepsy

“…Transplantation of fetal grafts containing CA3 cells into a lesioned CA3 region significantly restores the injuryinduced loss of GAD-and CB-positive interneurons in the TLE hippocampus, likely via restitution of the disrupted circuitry [89,90] . However, fetal CA1 cell grafts do not induce interneurons that increa se inhibition in the host [19,91,92] .…”

Reduction of seizures by transplantation of cortical GABAergic interneuron precursors into Kv1.1 mutant mice

“…Whether cell transplantation can be developed as an alternative therapeutic intervention for epilepsy requires investigation. Transplantation into the substantia nigra or hippocampus has resulted in modest suppression of evoked discharge; however, these studies did not demonstrate functional integration of transplanted cells within host circuits and did not provide evidence for a reduction of spontaneous electrographic seizures (1)(2)(3)(4). Furthermore, prior transplantation strategies did not focus on generation of a specific cell type from grafted cells.…”

Is exposure to enriched environment beneficial for functional post-lesional recovery in temporal lobe epilepsy?

“…The structural changes in the hippocampus comprise partial degeneration of CA1 and CA3 pyramidal neurons and dentate hilar neurons ( Fig. 1; Rao et al, 2006), reductions in gamma-amino butyric acid positive (GABA-ergic) interneurons (Shetty andTurner, 2000, 2001), loss of the calcium binding protein calbindin in dentate granule cells (Nagerl et al, 2000;Shetty and Hattiangady, 2007), and abnormal sprouting of dentate granule cell, entorhinal, and CA3 axons (Shetty and Turner, 1997;Shetty, 2002;Shetty et al, 2005;Siddiqui and Joseph, 2005;Wozny et al, 2005). The axons of dentate granule cells (hippocampal mossy fibers) branch out of the dentate hilus and abnormally innervate the dentate inner molecular layer in TLE, a phenomenon known as aberrant mossy fiber sprouting (Tauck and Nadler, 1985;Sutula et al, 1989;Okazaki et al, 1995;Shetty and Turner, 1997;Shetty et al, 2003;Ikegaya, 2004, 2005).…”