Synaptic Reorganization in the Hippocampus Induced by Abnormal Functional Activity

Sutula, Thomas P.; He, Xing; Cavazos, Jose ́E.; Scott, Grayson

doi:10.1126/science.2449733

Cited by 874 publications

(434 citation statements)

References 32 publications

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“…Although the role of mossy fiber sprouting in epileptogenesis has been challenged (Elmer et al, 1997;Nissinen et al, 2001), in addition to astrogliosis, mossy fiber sprouting is one of the characteristic histopathological findings in TLE (Kharatishvili et al, 2006;Pitkanen et al, 2007;Represa et al, 1993;Sloviter et al, 2006;Sutula et al, 1988). The loss of normal postsynaptic targets of granule neurons may be the cause for mossy fiber sprouting, an hypothesis supported by findings that the degree of mossy fiber sprouting is correlated to the degree of neuronal cell loss (Cavazos and Cross, 2006).…”

Section: Epileptogenesismentioning

confidence: 99%

The adenosine kinase hypothesis of epileptogenesis

Boison

2008

Progress in Neurobiology

208

210

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Current therapies for epilepsy are largely symptomatic and do not affect the underlying mechanisms of disease progression, i.e. epileptogenesis. Given the large percentage of pharmacoresistant chronic epilepsies, novel approaches are needed to understand and modify the underlying pathogenetic mechanisms. Although different types of brain injury (e.g. status epilepticus, traumatic brain injury, stroke) can trigger epileptogenesis, astrogliosis appears to be a homotypic response and hallmark of epilepsy. Indeed, recent findings indicate that epilepsy might be a disease of astrocyte dysfunction. This review focuses on the inhibitory neuromodulator and endogenous anticonvulsant adenosine, which is largely regulated by astrocytes and its key metabolic enzyme adenosine kinase (ADK). Recent findings support the "ADK hypothesis of epileptogenesis": (i) Mouse models of epileptogenesis suggest a sequence of events leading from initial downregulation of ADK and elevation of ambient adenosine as an acute protective response, to changes in astrocytic adenosine receptor expression, to astrocyte proliferation and hypertrophy (i.e. astrogliosis), to consequential overexpression of ADK, reduced adenosine and -finally -to spontaneous focal seizure activity restricted to regions of astrogliotic overexpression of ADK. (ii) Transgenic mice overexpressing ADK display increased sensitivity to brain injury and seizures. (iii) Inhibition of ADK prevents seizures in a mouse model of pharmacoresistant epilepsy. (iv) Intrahippocampal implants of stem cells engineered to lack ADK prevent epileptogenesis. Thus, ADK emerges both as a diagnostic marker to predict, as well as a prime therapeutic target to prevent, epileptogenesis.

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Section: Epileptogenesismentioning

confidence: 99%

The adenosine kinase hypothesis of epileptogenesis

Boison

2008

Progress in Neurobiology

208

210

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“…Axons of cortical pyramidal cells sprout following denervation (Salin et al, 1995). In the hippocampus, axons of both CA3 pyramidal cells (McKinney et al, 1997) and dentate granule cells (Sutula et al, 1988) undergo a reactive sprouting in response to loss of their post synaptic targets. The targets of novel mossy fibre collaterals may aid the expression of epileptiform activity.…”

Section: Does An Epileptic Brain Emerge From Developmental and Repairmentioning

confidence: 99%

Mesial temporal lobe epilepsy: A pathological replay of developmental mechanisms?

Cohen

Navarro

Duigou

et al. 2003

Biology of the Cell

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“…The kindling model of experimental epileptogenesis involves the generation of spontaneous seizures together with reorganization of mossy fiber synapses (McNamara, 1988;Sutula et al, 1988;Ben-Ari and Represa, 1990;Cavazos et al, 1991). It is interesting that together with synaptic reorganization of mossy fiber projections there appeared new [3H]kainate binding sites in the infrapyramidal cell layer of the CA3 subregion (Ben-Ari and Represa, 1990).…”

Section: Excitotoxicitymentioning

confidence: 99%

Kainate receptors in hippocampal CA3 subregion: evidence for a role in regulating neurotransmitter release

Malva

Carvalho

1998

Neurochemistry International

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The hippocampal CA3 subregion of the rat is characteristically enriched in kainate receptors. At the synaptic level, the subcellular localization of these receptors is still a matter of debate. The CA3 pyramidal cells are particularly sensitive to excitotoxicity induced by kainate, which is in agreement with the high levels of kainate receptors in the stratum lucidum of the hippocampal CA3 subregion. Immunocytochemical studies, using antibodies against kainate receptor subunits, clearly demonstrated the presence of postsynaptic kainate receptors. However, it was not possible at the time to identify the activity of postsynaptic kainate receptors as mediators of the synaptic transmission. There are also reports showing the labeling of unmyelinated axons and nerve terminals with antibodies against kainate receptor subunits. The evidence for the presence of presynaptic kainate receptors in the hippocampus is further substantiated by the demonstration that stimulation of kainate receptors in synaptosomes isolated from the rat hippocampal CA3 subregion increases the intracellular free Ca 2÷ concentration ([Ca2+]~) coupled to the release of glutamate. These results support the model proposed by Coyle (1983), in which the excitotoxicity induced by kainate involves the activation of presynaptic kainate receptors, causing the release of glutamate. According to this model, the neurotoxic effect of kainate in the rat hippocampal CA3 subregion involves a direct effect on presynaptic kainate receptors and an indirect effect on postsynaptic glutamate receptors due to the enhanced release of glutamate.

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Synaptic Reorganization in the Hippocampus Induced by Abnormal Functional Activity

Cited by 874 publications

References 32 publications

The adenosine kinase hypothesis of epileptogenesis

The adenosine kinase hypothesis of epileptogenesis

Mesial temporal lobe epilepsy: A pathological replay of developmental mechanisms?

Kainate receptors in hippocampal CA3 subregion: evidence for a role in regulating neurotransmitter release

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