Hostname: page-component-8448b6f56d-42gr6 Total loading time: 0 Render date: 2024-04-19T05:12:55.892Z Has data issue: false hasContentIssue false
  • English
  • Français

Uncoupling of astrogliosis from epileptogenesis in adenosine kinase (ADK) transgenic mice

Published online by Cambridge University Press:  13 August 2009

Tianfu Li ,
Jing-Quan Lan  and
Detlev Boison
Tianfu Li
Affiliation:
R. S. Dow Neurobiology Laboratories, Legacy Research, Portland, OR 97232, USA
Jing-Quan Lan
Affiliation:
R. S. Dow Neurobiology Laboratories, Legacy Research, Portland, OR 97232, USA
Detlev Boison*
Affiliation:
R. S. Dow Neurobiology Laboratories, Legacy Research, Portland, OR 97232, USA
*
Correspondence should be addressed to: Detlev Boison, R. S. Dow Neurobiology Laboratories, Legacy Research, Portland, OR 97232, USA phone: (503) 413 1754 fax: (503) 413 5465 email: dboison@downeurobiology.org
Get access Rights & Permissions [Opens in a new window]

Abstract

The astrocytic enzyme adenosine kinase (ADK) is a key negative regulator of the brain’s endogenous anticonvulsant adenosine. Astrogliosis with concomitant upregulation of ADK is part of the epileptogenic cascade and contributes to seizure generation. To molecularly dissect the respective roles of astrogliosis and ADK-expression for seizure generation, we used a transgenic approach to uncouple ADK-expression from astrogliosis: in Adk-tg mice the endogenous Adk-gene was deleted and replaced by a ubiquitously expressed Adk-transgene with novel ectopic expression in pyramidal neurons, resulting in spontaneous seizures. Here, we followed a unique approach to selectively injure the CA3 of these Adk-tg mice. Using this strategy, we had the opportunity to study astrogliosis and epileptogenesis in the absence of the endogenous astrocytic Adk-gene. After triggering epileptogenesis we demonstrate astrogliosis without upregulation of ADK, but lack of seizures, whereas matching wild-type animals developed astrogliosis with upregulation of ADK and spontaneous recurrent seizures. By uncoupling ADK-expression from astrogliosis, we demonstrate that global expression levels of ADK rather than astrogliosis per se contribute to seizure generation.

Keywords

Astrogliosisseizureskainic acidepileptogenesisCA3
Type
Research Article
Information
Neuron Glia Biology , Volume 4 , Issue 2 , May 2008 , pp. 91 - 99
Copyright
Copyright © Cambridge University Press 2009

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Bjorklund, O., Shang, M.M., Tonazzini, I., Dare, E. and Fredholm, B.B. (2008) Adenosine A(1) and A(3) receptors protect astrocytes from hypoxic damage. European Journal of Pharmacology 596, 6–13.CrossRefGoogle Scholar
Boison, D. (2006) Adenosine kinase, epilepsy and stroke: mechanisms and therapies. Trends in Pharmacological Science 27, 652–658.CrossRefGoogle ScholarPubMed
Boison, D. (2007) Adenosine-based cell therapy approaches for pharmacoresistant epilepsies. Neurodegeneration Disease 4, 28–33.CrossRefGoogle ScholarPubMed
Boison, D. (2008a) The adenosine kinase hypothesis of epileptogenesis. Progress in Neurobiology 84, 249–262.CrossRefGoogle ScholarPubMed
Boison, D. (2008b) Astrogliosis and adenosine kinase: a glial basis of epilepsy. Future Neurology 3, 221–224.CrossRefGoogle Scholar
Boison, D., Scheurer, L., Zumsteg, V., Rülicke, T., Litynski, P., Fowler, B. et al. (2002) Neonatal hepatic steatosis by disruption of the adenosine kinase gene. Proceedings of the National Academy of Sciences of the U.S.A. 99, 6985–6990.CrossRefGoogle ScholarPubMed
Fedele, D.E., Gouder, N., Güttinger, M., Gabernet, L., Scheurer, L., Rulicke, T. et al. (2005) Astrogliosis in epilepsy leads to overexpression of adenosine kinase resulting in seizure aggravation. Brain 128, 2383–2395.CrossRefGoogle ScholarPubMed
Gouder, N., Scheurer, L., Fritschy, J.-M. and Boison, D. (2004) Overexpression of adenosine kinase in epileptic hippocampus contributes to epileptogenesis. Journal of Neuroscience 24, 692–701.CrossRefGoogle ScholarPubMed
Halassa, M.M., Fellin, T. and Haydon, P.G. (2007) The tripartite synapse: roles for gliotransmission in health and disease. Trends in Molecular Medicine 13, 54–63.CrossRefGoogle ScholarPubMed
Haydon, P.G. and Carmignoto, G. (2006) Astrocyte control of synaptic transmission and neurovascular coupling. Physiological Reviews 86, 1009–1031.CrossRefGoogle ScholarPubMed
Iadecola, C. and Nedergaard, M. (2007) Glial regulation of the cerebral microvasculature. Natural Neuroscience 10, 1369–1376.CrossRefGoogle ScholarPubMed
Kumaria, A., Tolias, C. and Burnstock, G. (2008) ATP signalling in epilepsy. Purinergic Signalling 4, 339–346.CrossRefGoogle ScholarPubMed
Lado, F.A. and Moshe, S.L. (2008) How do seizures stop? Epilepsia 49, 1651–1664.CrossRefGoogle ScholarPubMed
Li, T., Lan, J.Q., Fredholm, B.B., Simon, R.P. and Boison, D. (2007a) Adenosine dysfunction in astrogliosis: cause for seizure generation? Neuron Glia Biology 3, 353–366.CrossRefGoogle ScholarPubMed
Li, T., Ren, G., Lusardi, T., Wilz, A., Lan, J.Q., Iwasato, T. et al. (2008) Adenosine kinase is a target for the prediction and prevention of epileptogenesis in mice. Journal of Clinical Investment 118, 571–582.Google ScholarPubMed
Li, T., Steinbeck, J.A., Lusardi, T., Koch, P., Lan, J.Q., Wilz, A. et al. (2007b) Suppression of kindling epileptogenesis by adenosine releasing stem cell-derived brain implants. Brain 130, 1276–1288.CrossRefGoogle ScholarPubMed
Martin, E.D., Fernandez, M., Perea, G., Pascual, O., Haydon, P.G., Araque, A. et al. (2007) Adenosine released by astrocytes contributes to hypoxia-induced modulation of synaptic transmission. Glia 55, 36–45.CrossRefGoogle ScholarPubMed
Oberheim, N.A., Tian, G.F., Han, X., Peng, W., Takano, T., Ransom, B. et al. (2008) Loss of astrocytic domain organization in the epileptic brain. Journal of Neuroscience 28, 3264–3276.CrossRefGoogle ScholarPubMed
Park, J. and Gupta, R.S. (2008) Adenosine kinase and ribokinase – the RK family of proteins. Cellular and Molecular Life Sciences 65, 2875–2896.CrossRefGoogle ScholarPubMed
Pascual, O., Casper, K.B., Kubera, C., Zhang, J., Revilla-Sanchez, R., Sul, J.Y. et al. (2005) Astrocytic purinergic signaling coordinates synaptic networks. Science 310, 113–116.CrossRefGoogle ScholarPubMed
Pignataro, G., Maysami, S., Studer, F.E., Wilz, A., Simon, R.P. and Boison, D. (2008) Downregulation of hippocampal adenosine kinase after focal ischemia as potential endogenous neuroprotective mechanism. Journal of Cerebral Blood Flow and Metabolism 28, 17–23.CrossRefGoogle ScholarPubMed
Pignataro, G., Simon, R.P. and Boison, D. (2007) Transgenic overexpression of adenosine kinase aggravates cell death in ischemia. Journal of Cerebral Blood Flow and Metabolism 27, 1–5.CrossRefGoogle ScholarPubMed
Pitkanen, A. and Lukasiuk, K. (2009) Molecular and cellular basis of epileptogenesis in symptomatic epilepsy. Epilepsy Behavior 14 (Suppl 1), 16–25.CrossRefGoogle ScholarPubMed
Ravizza, T., Gagliardi, B., Noe, F., Boer, K., Aronica, E. and Vezzani, A. (2008) Innate and adaptive immunity during epileptogenesis and spontaneous seizures: evidence from experimental models and human temporal lobe epilepsy. Neurobiology Disease 29, 142–160.CrossRefGoogle ScholarPubMed
Rebola, N., Coelho, J.E., Costenla, A.R., Lopes, L.V., Parada, A., Oliveira, C.R. et al. (2003) Decrease of adenosine A1 receptor density and of adenosine neuromodulation in the hippocampus of kindled rats. European Journal of Neuroscience 18, 820–828.CrossRefGoogle ScholarPubMed
Shinoda, S., Schindler, C.K., Meller, R., So, N.K., Araki, T., Yamamoto, A. et al. (2004) Bim regulation may determine hippocampal vulnerability after injurious seizures and in temporal lobe epilepsy. Journal of Clinical Investment 113, 1059–1068.CrossRefGoogle ScholarPubMed
Studer, F.E., Fedele, D.E., Marowsky, A., Schwerdel, C., Wernli, K., Vogt, K. et al. (2006) Shift of adenosine kinase expression from neurons to astrocytes during postnatal development suggests dual functionality of the enzyme. Neuroscience 142, 125–137.CrossRefGoogle ScholarPubMed
Szybala, C., Pritchard, E.M., Wilz, A., Kaplan, D.L. and Boison, D. (2009) Antiepileptic effects of silk-polymer based adenosine release in kindled rats. Experimental Neurology doi:10.1016/j.expneurol.2009.05.18.CrossRefGoogle ScholarPubMed
Tian, G.F., Azmi, H., Takano, T., Xu, Q.W., Peng, W.G., Lin, J. et al. (2005) An astrocytic basis of epilepsy. Nature Medicine 11, 973–981.CrossRefGoogle ScholarPubMed
Vezzani, A. (2008) Epileptogenic role of astrocyte dysfunction. Epilepsy Currents 8, 46–47.CrossRefGoogle ScholarPubMed
Wetherington, J., Serrano, G. and Dingledine, R. (2008) Astrocytes in the epileptic brain. Neuron 58, 168–178.CrossRefGoogle ScholarPubMed