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The Journal of Neuroscience, November 9, 2005, 25(45):10337-10338; doi:10.1523/JNEUROSCI.4114-05.2005
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Not Every Graft Has What It Takes to Attract a Mossy Fiber
Yevgenia Kozorovitskiy Department of Psychology and Program in Neuroscience, Princeton University, Princeton, New Jersey 08544
Although the adult mammalian brain maintains high levels of structural plasticity and can change dramatically in response to neural activity (Zito and Svoboda, 2002
), not all structural change is adaptive. For example, neural activity in status epilepticus is associated with several structural abnormalities. One consequence of limbic seizures in animal models and in human temporal lobe epilepsy (TLE) is the excitotoxic death of neurons in the CA3 region and in the hilus of the dentate gyrus and the ensuing aberrant mossy fiber sprouting (when axon collaterals from dentate gyrus granule cells invade the molecular layer and establish abnormal connections with other neurons, including excitatory kainate-receptor-driven synapses on granule cells themselves) (Scharfman et al., 2003
The authors began with a unilateral intracerebroventricular injection of kainic acid (KA) into the brains of adult rats (Fig. 1). This excitotoxic agonist for the AMPA/KA glutamatergic receptor leads to limbic seizures and cell death in the CA3 region and in the hilus. Applying Timm's silver sulfide stain, which labels zinc-containing vesicles in axonal fibers, to sections of the hippocampus, the authors confirmed that mossy fibers invaded the dentate gyrus supragranular layer in lesioned animals, but not in controls [Shetty et al. (2005
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Figure 1. Simplified schematic of the experiments and the results presented by Shetty et al. (2005
Meanwhile, Shetty et al. harvested brains of rats on embryonic day 19 and prepared cell suspensions containing either CA1 or CA3 neurons. Then, at two different time points after KA injection, 4 or 45 d, the authors introduced the transplants, placing the grafts as close as possible to the degenerated CA3 layer. Shetty et al. waited an entire year before looking at hippocampal structure of the rats with the transplants. Because 1 year comprises a substantial part of the rat's life span (typically <3 years), this timing allowed the authors to gather information about the relatively long-term outcome after transplants. Nuclear Nissl staining confirmed lesion effectiveness in the lesion-only group and was used to localize transplants in the grafted animals. New transplanted neurons were evident in animals that received grafts containing either CA1 or CA3 pyramidal cells. Interestingly, in a separate experiment, the authors found that the CA1 and the CA3 cells within the transplants exhibited divergent and cell-type-specific patterns of axonal growth. Transplanted CA3 cells projected heavily to the CA1 field and other regions typically innervated by CA3 pyramidal neurons. On the other hand, transplanted CA1 cells, while still projecting to some of the same regions, showed connectivity patterns that were more similar to those of normal CA1 pyramidal cells [Shetty et al. (2005Although the goal of neuronal replacement per se was accomplished with the transplants containing either CA1 or CA3 neurons, the degree of mossy fiber sprouting, measured either as the width of the mossy fiber bundle or as the density of Timm's granules, differed dramatically between the two types of grafts. With the CA1 grafts, administered either 4 or 45 d after KA injection, the amount of mossy fiber sprouting 1 year later was the same as in animals that received lesions alone. Thus, while the transplanted cells had integrated into the new circuitry, epileptogenic architecture persisted in the dentate gyrus. However, the CA3 grafts effectively decreased mossy fiber sprouting when administered early (4 d) or relatively late (45 d) after hippocampal injury [Shetty et al. (2005
In summary, Shetty et al. elucidated the following novel function for fetal brain cells that goes beyond cell replacement: to reconfigure potentially well established aberrant circuits by providing appropriate postsynaptic targets. These experiments make an important scientific contribution to the search for a cure for TLE and other types of seizures, yet many questions remain for future investigation. For one, how wide is the temporal window during which the graft must be administered to inhibit mossy fiber sprouting? More importantly, does the degree of mossy fiber sprouting inhibition in KA-lesioned animals after transplants actually correlate with functional or behavioral recovery? This question can be pursued explicitly in animals that, unlike the ones used in this series of studies, show a substantial level of spontaneous recurrent seizures. In addition to assessing seizure frequency in animals before and after the transplant, it would be interesting to examine aspects of hippocampal-dependent learning in these animals. Although the likely clinical applications of the experiments by Shetty et al. remain to be seen in the future, we have already learned from their work the following key lesson in basic neuroscience: the strength of a neuron's identity, even in the case of a very young cell, can override the chemical drive of the surrounding milieu.
Received Sep 27, 2005; revised October 10, 2005; accepted October 10, 2005.
Footnotes
Correspondence should be addressed to Yevgenia Kozorovitskiy, Department of Psychology, Princeton University, Princeton, NJ 08544. E-mail: yevgenia{at}princeton.edu.
Copyright © 2005 Society for Neuroscience 0270-6474/05/2510337-02$15.00/0
Review of Shetty et al. (http://www.jneurosci.org/cgi/content/full/25/37/8391)
References
Epsztein J, Represa A, Jorquera I, Ben-Ari Y, Crepel V (2005) Recurrent mossy fibers establish aberrant kainate receptor-operated synapses on granule cells from epileptic rats. J Neurosci 25: 8229-8239.
[Abstract/Free Full Text] Parent JM, Lowenstein DH (2002) Seizure-induced neurogenesis: are more new neurons good for an adult brain? Prog Brain Res 135: 121-131.[Medline]
Scharfman HE, Sollas AL, Berger RE, Goodman JH (2003) Electrophysiological evidence of monosynaptic excitatory transmission between granule cells after seizure-induced mossy fiber sprouting. J Neurophysiol 90: 2536
[Abstract/Free Full Text] Shetty AK, Zaman V, Hattiangady B (2005) 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. J Neurosci 25: 8391-8401.
[Abstract/Free Full Text] Zito K, Svoboda K (2002) Activity-dependent synaptogenesis in the adult mammalian cortex. Neuron 35: 1015-1017.[CrossRef][ISI][Medline]
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