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The Journal of Neuroscience, September 14, 2005, 25(37):8391-8401; doi:10.1523/JNEUROSCI.1538-05.2005

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Development/Plasticity/Repair
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

Ashok K. Shetty, Vandana Zaman, and Bharathi Hattiangady

Department of Surgery (Neurosurgery), Duke University Medical Center, Durham, North Carolina 27710, and Medical Research and Surgery Services, Veterans Affairs Medical Center, Durham, North Carolina 27705

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.

Key words: brain repair; efferent graft projections; graft–host connectivity; hippocampal CA3 cells; kainic acid; mossy fiber sprouting; neural grafting; neural transplant integration

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Received April 19, 2005; revised July 29, 2005; accepted July 31, 2005.

This article has been cited by other articles:

				A. K. Shetty and B. Hattiangady Concise Review: Prospects of Stem Cell Therapy for Temporal Lobe Epilepsy Stem Cells, October 1, 2007; 25(10): 2396 - 2407. [Abstract] [Full Text] [PDF]

				B. Hattiangady, B. Shuai, J. Cai, T. Coksaygan, M. S. Rao, and A. K. Shetty Increased Dentate Neurogenesis After Grafting of Glial Restricted Progenitors or Neural Stem Cells in the Aging Hippocampus Stem Cells, August 1, 2007; 25(8): 2104 - 2117. [Abstract] [Full Text] [PDF]

				T. Bliss, R. Guzman, M. Daadi, and G. K. Steinberg Cell Transplantation Therapy for Stroke Stroke, February 1, 2007; 38(2): 817 - 826. [Abstract] [Full Text] [PDF]

				Y. Kozorovitskiy Not Every Graft Has What It Takes to Attract a Mossy Fiber J. Neurosci., November 9, 2005; 25(45): 10337 - 10338. [Full Text] [PDF]

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