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Neuronal loss in temporal lobe epilepsy From Wikipedia, the free encyclopedia Neuronal loss in temporal lobe epilepsy(TLE) is a type of hippocampal sclerosis found in temporal lobe epileptic patients and animal models of epilepsy. This neuropathology is first founded in 1880 in patients with TLE[1]. Temporal lobe epilepsy occurs after a precipitation injury which causes brain damage. There are a variety of conditions can cause the damages such as Traumatic brain injury, neurodegenerative diseases, stroke,brain tumor, status epilepticus etc.[2] After the initial damage, there will be a seizure-free period before recurrent seizure, called latent period.[3] The range of latent period varies a lot, from several weeks to years.[4] In order to understand the pathology of temporal lobe epilepsy, scientists developed several animal models to represent the temporal lobe epilepsy in human. The three most used models are[5] kainic acid model,[6], pilocarpine model,[5] kindling model[7]. By using animal models, neuronal loss starts during the initial brain damage and stops at a certain point. Apoptosis[8] and necrosis[8] both involves in the process of neuronal loss. Neuronal loss is the most common pathology in TLE, which presents in 40 to 70% of TLE patients. This pathology precedes the seizure formation,[9] and the region of seizure onset has the highest amount of neuronal loss.[10] Based on the above evidence, neuronal loss has contribution toward seizure formation. It is debatable that whether neuronal loss is the origin of chronic seizures in TLE patients, or just a contribution for seizure formation, different researches show contradictory result.[11][12] Contents [hide] 1 Mechanism of neuronal loss 2 Pattern and time scale of neuronal loss 3 Effects of neuronal loss 3.1 Granule cell dispersion 3.1.1 Reelin role in temporal lobe epilepsy 3.2 Mossy fiber sprouting 3.2.1 Aberrant mossy fiber sprouting 3.2.2 Effects of aberrant mossy fiber sprouting 4 See also 5 References Mechanism of neuronal loss[edit]

Main article: Excitotoxicity Cell loss is the result of glutamate-mediated excitotoxicity since large amount of seizure induced calcium ions Ca2+ enter the cells by the stimulation of glutamate and other similar neurotransmitters.[13] The excessive calcium ion will cause oxidative stress, organelle swelling, and rupture of intracellular membranes.[14] Even though there is no direct evidence to show neuronal loss is the trigger for chronic seizure formation, it is certain that neuronal loss contributes to the intensity of chronic seizure.[12] Pattern and time scale of neuronal loss[edit]

Different types and regions of neurons suffer different severity of injuries. In the case of temporal lobe epilepsy, neuronal loss mainly happens in the CA1 and CA3 area of the hippocampus[15][16]. By studying hippocampal specimens from TLE patients and animal models, there is an extensive damage of mossy cells and inhibitory interneurons in the hilar region.[17][18][19] Granule cells in the dentate gyrus are more resistant, and they suffer less damage, but still noticeable.[15] By using animal models to study when neuronal loss started, researchers found out that neuronal loss started immediately after injecting the chemicalcovulsant or using electrical stimulation to trigger the initial injury. The affected size of neuronal loss started to increase up to one months, and there are no further degeneration of neurons that are noticeable.[20][15] Effects of neuronal loss[edit]

Inhibitory interneurons and mossy cells are two mainly types of neuronal loss that are found in epileptic patients and animal models. The loss of inhibitory interneurons is proposed to increase hyperexcitability of the neuronal populations in the hippocampus[21] due to the loss of the GABA-mediated inhibition. By using animal model, studies show that the loss of inhibitory interneurons will increase the excitatory postsynaptic potentials(EPSPs) in the granule cells, and the granule cells will discharge more action potentials than controls.[19] Beside the loss of the GABAergic interneurons, the loss of mossy cells are proposed to cause recurrent seizure. Mossy cells receive different synaptic inputs from different neurons including granule cells and inhibitory neurons in the hilar regions, and their loss will lead to granule cell hyperexcitability. According to "dormant basket cell" hypothesis, mossy cells normally excited inhibitory basket cells, and the basket cells can make the granule cell less excitable.[22] The loss of mossy cells will reduce the excitability of the basket cells and reduce the threshold of action potentials of the granule cells.[22] Neuronal loss has shown a direct impact toward the formation of granule cell dispersion and mossy fiber sprouting. Whether these abnormal structure will contribute to seizure is still debatable. Granule cell dispersion[edit] Granule cell dispersion is one of the abnormal structure that was shown in the patients' brain of temporal lobe epilepsy.[23] It belongs to a type of developmental migration. It was first described in 1990.[24] In a normal situation, the granule cell layer in dentate gyrus should be tightly packed, forming a uniform, and laminated cell layer. There are no monosynaptic connections between granule cells.[25] Because of the unique structure, dentate gyrus is considered as a high-resistance filter or gate, hyperextatibility can be prevented by the role of dentate gyrus.[25] During the temporal lobe epilepsy, the closely packed lamination was loss,[24] because the granule cells become loosely distributed in the dentate granule. In order to reconnect each granule cells, the axons might need to extend to deeper molecular layer to contact with the dendrites of different located neurons. This might increase the granule cell interconnectivity and hyperextatibility.[18] Reelin role in temporal lobe epilepsy[edit] Reelin is an extracellular matrix protein that is required for normal neuronal lamination in humans, and the lack of this expression can lead to migration defect associated with temporal lobe epilepsy.[26] Granule cell migration defects in the dentate gyrus are correlative to the reduced expression of reelin mRNA.[27] It has been showed that reelin can stabilize the lamination structure of granule cell.[27] Also, reelin regulates the layer formation of cerebral cortex during brain development.[28] Reelin deficiency correlates with granule cell dispersion in temporal lobe epileptic patients and epileptic animal models.[29] Mossy fiber sprouting[edit] Mossy fiber are the axons of granule cells in the dentate gyrus. They project into the dentate hilus and stratum lucidum of CA3 in mammals.[30] They provide synaptic input to excitatory and inhibitory neurons in the hilus and area CA3.[31] In the normal situation, mossy fibers seldom synapse with other granule cells, which make granule cells lack of monosynaptic connections.[25] Aberrant mossy fiber sprouting[edit] Mossy fiber sprouting are first found in patients with TLE in 1974[32] and animal models in 1985[33]. The increase spread of mossy fiber interested scientists since 1980s.[33] By using Timm stainning, it shows that mossy fiber in epileptic patients and animal models sprout much larger than the normal brain.[25] During the initial injury of the brain, mossy cells are degenerated. Since granule cell dentrites innervated by mossy cells, the loss of mossy cell cause loss of connection between mossy cells and granule cells. The loss will trigger the other granule cells axons(mossy fibers) to reconnect to the affected granule cells by sprouting the mossy fibers to the dendrites.[25] This is an example of synaptic reorganization. Both in epileptic patients and animal models showed a time-dependent increase of mossy fiber sprouting in the dentate gyrus. By using animal models, mossy fiber sprouting can be observed 1 week after injecting chemical-covulsants or using stimulation, and the abnormal structure will increase its size for up to two months.[34] There is an association for aberrant mossy fiber sprouting after injuries of the brain and neuronal cell loss.[35][36] During the initial injury of the brain, mossy cells are degenerated. Since granule cell dentrites innervated by mossy cells, the loss of mossy cell cause loss of connection between mossy cells and granule cells. The loss will trigger the other granule cells axons(mossy fibers) to reconnect to the affected granule cells by sprouting the mossy fibers to the dendrites.[25] Effects of aberrant mossy fiber sprouting[edit] Since the first discovery of aberrant mossy fiber sprouting,[33] scientists are interested to find out whether this abnormal structure is epileptogenic, compensatory, or neither. Different researches show different results. The majority speculates that the abnormal mossy fiber sprouting formes an excitatory circuit in the dentate gyrus which could increase the seizure frequency and intensity.[37] By stimulating the aberrant mossy fiber sprouting area, it shows that the area produced an increase of excitatory postsynaptic potential response.[33] Also, by using intracellular recording, it shows the synaptic connections in the aberrant mossy fiber sprouting, which seldom happens in normal dentate gyrus. It means the area contains monosynaptic excitatory connections.[38] This evidence shows that sprouted mossy fibers connect granule cells together and produce new excitatory connections. In contrast, other researches show the aberrant mossy fiber sprouting can inhibit the seizure formation[22][39] since sprouted mossy fibers synapse with inhibitory baseket cell which will create an inhibitory circuit in the dentate gyrus. Besides, inhibitory neurotransmitter NPY[40] and GABA[41] are found releasing in aberrant mossy fibers sprouting.