Seizure Disorders in Down Syndrome

Pueschel, Siegfried M.; Louis, Sydney; McKnight, Pamela

doi:10.1001/archneur.1991.00530150088024

Cited by 153 publications

(82 citation statements)

References 20 publications

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“…Remarkably, although BDNF enhances excitatory neurotransmission, it potentiates GABAergic inhibition in the epileptic brain (Koyama and Ikegaya, 2005). Furthermore, DS patients have a greater propensity to develop epilepsy (Pueschel et al, 1991), and, thus, the glutamatergic positive-feedback loop model (Fig. 9) may also be relevant to the development of epilepsy in DS patients.…”

Section: Discussionmentioning

confidence: 99%

An Increase in Basal BDNF Provokes Hyperactivation of the Akt-Mammalian Target of Rapamycin Pathway and Deregulation of Local Dendritic Translation in a Mouse Model of Down's Syndrome

Troca-Marín

Alves-Sampaio²,

Montesinos³

2011

Journal of Neuroscience

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As in other diseases associated with mental retardation, dendrite morphology and synaptic plasticity are impaired in Down's syndrome (DS). Both these features of neurons are critically influenced by BDNF, which regulates local dendritic translation through phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin (mTOR) and Ras-ERK signaling cascades. Here we show that the levels of BDNF and phosphorylated Akt-mTOR (but not Ras-ERK) pathway proteins are augmented in hippocampal dendrites of Ts1Cje mice, a DS model. Consequently, the rate of local dendritic translation is abnormally high and the modulatory effect of exogenous BDNF is lost. Interestingly, rapamycin (a Food and Drug Administration-approved drug) restores normal levels of phosphorylated Akt-mTOR proteins and normal rates of local translation in Ts1Cje neurons, opening new therapeutic perspectives for DS. The NMDAR inhibitors APV, MK-801, and memantine also restore the normal levels of phospho-mTOR in dendrites of Ts1Cje hippocampal neurons. We propose a model to explain how BDNF-mediated regulation of local translation is lost in the Ts1Cje hippocampus through the establishment of a glutamatergic positive-feedback loop. Together, these findings help elucidate the mechanisms underlying altered synaptic plasticity in DS.

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Section: Discussionmentioning

confidence: 99%

An Increase in Basal BDNF Provokes Hyperactivation of the Akt-Mammalian Target of Rapamycin Pathway and Deregulation of Local Dendritic Translation in a Mouse Model of Down's Syndrome

Troca-Marín

Alves-Sampaio²,

Montesinos³

2011

Journal of Neuroscience

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“…For example, in the olfactory bulb and neocortex the newly-born cells are mainly inhibitory (GABAergic) (reviewed in Cameron & Dayer, 2008). Reduced neurogenesis in these regions could result in relative disinhibition and, thus, could be regarded as a factor contributing to epilepsy in DS (Goldberg-Stern et al, 2001;Menendez, 2005;Pueschel et al, 1991). In contrast, DG and cerebellar granule cells are excitatory (glutamatergic).…”

Section: Discussionmentioning

confidence: 99%

Deficiency of Adult Neurogenesis in the Ts65Dn Mouse Model of Down Syndrome

Belichenko¹,

Kleschevnikov²

2011

Genetics and Etiology of Down Syndrome

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“…later (Pueschel et al, 1991). Boys tend to have an earlier age onset, regardless of seizure type, although this may reflect the general male predominance in the infantile spasm group aged less than 1 year at onset.…”

Section: Genetics and Etiology Of Down Syndrome 242mentioning

confidence: 93%

“…Epilepsy in DS showed a bimodal distribution; in the younger age group, infantile spasms and tonic-clonic seizures with myoclonus are the main finding, whereas older patients often have partial simplex or partial complex seizures as well as tonic-clonic seizures (Pueschel et al, 1991).…”

Section: Clinical and Electrophysiological Featuresmentioning

confidence: 99%