Structural rearrangement of the dentate gyrus has been described as the underlying cause of many types of epilepsies, particularly temporal lobe epilepsy. It is said to occur when aberrant connections are established in the damaged hippocampus, as described in human epilepsy and experimental models. Computer modelling of the dentate gyrus circuitry and the corresponding structural changes has been used to understand how abnormal mossy fibre sprouting can subserve seizure generation observed in experimental models when epileptogenesis is induced by status epilepticus. The model follows the McCulloch-Pitts formalism including the representation of the nonsynaptic mechanisms. The neuronal network comprised granule cells, mossy cells, and interneurons. The compensation theory and the Hebbian and anti-Hebbian rules were used to describe the structural rearrangement including the effects of the nonsynaptic mechanisms on the neuronal activity. The simulations were based on neuroanatomic data and on the connectivity pattern between the cells represented. The results suggest that there is a joint action of the compensation theory and Hebbian rules during the inflammatory process that accompanies the status epilepticus. The structural rearrangement simulated for the dentate gyrus circuitry promotes speculation about the formation of the abnormal mossy fiber sprouting and its role in epileptic seizures. 1. Introduction Epileptic syndromes are a group of neurological disorders with different etiology and clinics characterized by recurrent seizures with excessive and hypersynchronous neuronal activity [1]. Nowadays, approximately 50 million people are affected with epilepsy and 40% of which are classified as temporal lobe epilepsy (TLE) [2]. The human TLE is frequently associated with neuronal loss in the hippocampus and dentate gyrus (DG) [3]. Throughout this degeneration, called hippocampal sclerosis, the granule cells are less affected. The neurotransmitter gamma-aminobutyric acid and proteins expressed in these cells are allegedly responsible for neuroprotection, increasing resistance to excitatory injury [4]. The DG has been proposed to be a gate for entry of intense neuronal activity into the hippocampus. However, in TLE, the synaptic reorganization involving the DG granule cells (abnormal sprouting of hippocampal mossy fibers) may act to reduce the DG filtration properties, increasing the propensity to intensify the neuronal activity and, therefore, the seizure propagation through the hippocampus and other limbic system structures [5]. Mossy fiber sprouting
References
[1]
J. Engel, Seizures and Epilepsy, Edited by F. A. Davis Company, F. A. Davis Company, Philadelphia, Pa, USA, 1989.
[2]
M. J. S. Fernandes, E. A. Cavalheiro, J. P. Leite, and D. S. Persike, “Temporal lobe epilepsy: cell death and molecular targets activity,” in Underlying Mechanisms of Epilepsy, F. S. Kaneez, Ed., pp. 117–134, InTech, Rijeka, Croatia, 2011.
[3]
A. K. Sharma, R. Y. Reams, W. H. Jordan, M. A. Miller, H. L. Thacker, and P. W. Snyder, “Mesial temporal lobe epilepsy: pathogenesis, induced rodent models and lesions,” Toxicologic Pathology, vol. 35, no. 7, pp. 984–999, 2007.
[4]
F. A. Guedes, O. Y. Galvis-Alonso, and J. P. Leite, “Plasticidade neuronal associada à epilepsia do lobo temporal mesial: insights a partir de Estudos em Humanos e em Modelos Animais,” Journal of Epilepsy and Clinical Neurophysiology, vol. 12, pp. 10–17, 2006.
[5]
P. S. Buckmaster, G. F. Zhang, and R. Yamawaki, “Axon sprouting in a model of temporal lobe epilepsy creates a predominantly excitatory feedback circuit,” Journal of Neuroscience, vol. 22, no. 15, pp. 6650–6658, 2002.
[6]
M. J. A. M. van Puttena, L. C. Liefaardb, M. Danhof, and R. A. Voskuyl, “Quantitative EEG analysis: a biomarker for epileptogenesis,” in Pharmacoresistance in Epilepsy-Modelling and Prediction of Disease Progression, C. Liefaard, Ed., pp. 51–67, 2008.
[7]
K. Morimoto, M. Fahnestock, and R. J. Racine, “Kindling and status epilepticus models of epilepsy: rewiring the brain,” Progress in Neurobiology, vol. 73, no. 1, pp. 1–60, 2004.
[8]
J. E. Franck, J. Pokorny, D. D. Kunkel, and P. A. Schwartzkroin, “Physiologic and morphologic characteristics of granule cell circuitry in human epileptic hippocampus,” Epilepsia, vol. 36, no. 6, pp. 543–558, 1995.
[9]
M. M. Okazaki, P. Molnár, and J. V. Nadler, “Recurrent mossy fiber pathway in rat dentate gyrus: synaptic currents evoked in presence and absence of seizure-induced growth,” Journal of Neurophysiology, vol. 81, no. 4, pp. 1645–1660, 1999.
[10]
J. P. Wuarin and F. E. Dudek, “Electrographic seizures and new recurrent excitatory circuits in the dentate gyrus of hippocampal slices from kainate-treated epileptic rats,” Journal of Neuroscience, vol. 16, no. 14, pp. 4438–4448, 1996.
[11]
W. W. Lytton, K. M. Hellman, and T. P. Sutula, “Computer models of hippocampal circuit changes of the kindling model of epilepsy,” Artificial Intelligence in Medicine, vol. 13, no. 1-2, pp. 81–97, 1998.
[12]
V. Santhakumar, I. Aradi, and I. Soltesz, “Role of mossy fiber sprouting and mossy cell loss in hyperexcitability: a network model of the dentate gyrus incorporating cell types and axonal topography,” Journal of Neurophysiology, vol. 93, no. 1, pp. 437–453, 2005.
[13]
R. J. Morgan and I. Soltesz, “Nonrandom connectivity of the epileptic dentate gyrus predicts a major role for neuronal hubs in seizures,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 16, pp. 6179–6184, 2008.
[14]
A. C. G. Almeida, A. M. Rodrigues, F. A. Scorza et al., “Mechanistic hypotheses for nonsynaptic epileptiform activity induction and its transition from the interictal to ictal state-Computational simulation,” Epilepsia, vol. 49, no. 11, pp. 1908–1924, 2008.
[15]
W. S. McCulloch and W. Pitts, “A logical calculus of the ideas immanent in nervous activity,” The Bulletin of Mathematical Biophysics, vol. 5, no. 4, pp. 115–133, 1943.
[16]
J. Dyhrfjeld-Johnsen, V. Santhakumar, R. J. Morgan, R. Huerta, L. Tsimring, and I. Soltesz, “Topological determinants of epileptogenesis in large-scale structural and functional models of the dentate gyrus derived from experimental data,” Journal of Neurophysiology, vol. 97, no. 2, pp. 1566–1587, 2007.
[17]
J. R. Wolff and G. P. Wagner, “Selforganization in synaptogenesis: interaction between the formation of excitatory and inhibitory synapses,” in Synergetics of the Brain, E. Basar, H. Flohr, H. Haken, and A. J. Mandell, Eds., pp. 50–59, Springer, Berlin, Germany, 1983.
[18]
I. E. Dammasch and G. P. Wagner, “On the properties of randomly connected McCulloch-Pitts networks: differences between input-constant and input-variant networks,” Cybernetics and Systems, vol. 15, no. 1-2, pp. 91–117, 1984.
[19]
I. E. Dammasch, G. P. Wagner, and J. R. Wolff, “Self-stabilization of neuronal networks I. The compensation algorithm for synaptogenesis,” Biological Cybernetics, vol. 54, no. 4-5, pp. 211–222, 1986.
[20]
M. Butz, K. Lehmann, I. E. Dammasch, and G. Teuchert-Noodt, “A theoretical network model to analyse neurogenesis and synaptogenesis in the dentate gyrus,” Neural Networks, vol. 19, no. 10, pp. 1490–1505, 2006.
[21]
I. E. Dammasch, G. P. Wagner, and J. R. Wolff, “Self-stabilization of neuronal networks. II. Stability conditions for synaptogenesis,” Biological Cybernetics, vol. 58, no. 3, pp. 149–158, 1988.
[22]
A. C. G. Almeida, A. M. Rodrigues, M. A. Duarte et al., “Biophysical aspects of the nonsynaptic epileptiform activity,” in Underlying Mechanisms of Epilepsy, F. S. Kaneez, Ed., pp. 189–218, InTech, Rijeka, Croatia, 2011.
[23]
L. J. Cromme and I. E. Dammasch, “Compensation type algorithms for neural nets: stability and convergence,” Journal of Mathematical Biology, vol. 27, no. 3, pp. 327–340, 1989.
[24]
J. Lisman, “A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory,” Proceedings of the National Academy of Sciences of the United States of America, vol. 86, no. 23, pp. 9574–9578, 1989.
[25]
J. T. Trachtenberg, B. E. Chen, G. W. Knott et al., “Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex,” Nature, vol. 420, no. 6917, pp. 788–794, 2002.
[26]
V. De Paola, A. Holtmaat, G. Knott et al., “Cell type-specific structural plasticity of axonal branches and boutons in the adult neocortex,” Neuron, vol. 49, no. 6, pp. 861–875, 2006.
[27]
J. E. Cavazos, G. Golarai, and T. P. Sutula, “Mossy fiber synaptic reorganization induced by kindling: time course of development, progression, and permanence,” Journal of Neuroscience, vol. 11, no. 9, pp. 2795–2803, 1991.
[28]
B. Adams, M. Lee, M. Fahnestock, and R. J. Racine, “Long-term potentiation trains induce mossy fiber sprouting,” Brain Research, vol. 775, no. 1-2, pp. 193–197, 1997.
[29]
U. Sayin, S. Osting, J. Hagen, P. Rutecki, and T. Sutula, “Spontaneous seizures and loss of axo-axonic and axo-somatic inhibition induced by repeated brief seizures in kindled rats,” Journal of Neuroscience, vol. 23, no. 7, pp. 2759–2768, 2003.
[30]
H. R. Pathak, F. Weissinger, M. Terunuma et al., “Disrupted dentate granule cell chloride regulation enhances synaptic excitability during development of temporal lobe epilepsy,” Journal of Neuroscience, vol. 27, no. 51, pp. 14012–14022, 2007.
[31]
S. W. Briggs and A. S. Galanopoulou, “Altered GABA signaling in early life epilepsies,” Neural Plasticity, vol. 2011, Article ID 527605, 16 pages, 2011.
[32]
I. Cohen, V. Navarro, S. Clemenceau, M. Baulac, and R. Miles, “On the origin of interictal activity in human temporal lobe epilepsy in vitro,” Science, vol. 298, no. 5597, pp. 1418–1421, 2002.
[33]
G. Huberfeld, L. Wittner, S. Clemenceau et al., “Perturbed chloride homeostasis and GABAergic signaling in human temporal lobe epilepsy,” Journal of Neuroscience, vol. 27, no. 37, pp. 9866–9873, 2007.
[34]
A. T. U. Schaefers, K. Grafen, G. Teuchert-Noodt, and Y. Winter, “Synaptic remodeling in the dentate gyrus, CA3, CA1, subiculum, and entorhinal cortex of mice: effects of deprived rearing and voluntary running,” Neural Plasticity, vol. 2010, Article ID 870573, 11 pages, 2010.
[35]
V. Santhakumar, R. Bender, M. Frotscher et al., “Granule cell hyperexcitability in the early post-traumatic rat dentate gyrus: the 'irritable mossy cell' hypothesis,” Journal of Physiology, vol. 524, no. 1, pp. 117–134, 2000.
[36]
J. V. Nadler, “The recurrent mossy fiber pathway of the epileptic brain,” Neurochemical Research, vol. 28, no. 11, pp. 1649–1658, 2003.
[37]
P. S. Buckmaster and F. H. Lew, “Rapamycin suppresses mossy fiber sprouting but not seizure frequency in a mouse model of temporal lobe epilepsy,” Journal of Neuroscience, vol. 31, no. 6, pp. 2337–2347, 2011.
[38]
J. G. R. Jefferys and H. L. Haas, “Synchronized bursting of CA1 hippocampal pyramidal cells in the absence of synaptic transmission,” Nature, vol. 300, no. 5891, pp. 448–450, 1982.
[39]
C. P. Taylor and F. E. Dudek, “Synchronous neural afterdischarges in rat hippocampal slices without active chemical synapses,” Science, vol. 218, no. 4574, pp. 810–812, 1982.
[40]
Z. Q. Xiong and J. L. Stringer, “Sodium pump activity, not glial spatial buffering, clears potassium after epileptiform activity induced in the dentate gyrus,” Journal of Neurophysiology, vol. 83, no. 3, pp. 1443–1451, 2000.
[41]
M. Frotscher, P. Jonas, and R. S. Sloviter, “Synapses formed by normal and abnormal hippocampal mossy fibers,” Cell and Tissue Research, vol. 326, no. 2, pp. 361–367, 2006.
[42]
W. W. Lytton, “Computer modelling of epilepsy,” Nature Reviews Neuroscience, vol. 9, no. 8, pp. 626–637, 2008.
