Article

Early Alterations of AMPA Receptors Mediate Synaptic Potentiation Induced by Neonatal Seizures

Department of Neurology, Division of Neuroscience, Children's Hospital, Boston, Massachusetts 02115, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 09/2008; 28(32):7979-90. DOI: 10.1523/JNEUROSCI.1734-08.2008
Source: PubMed

ABSTRACT

The highest incidence of seizures during lifetime is found in the neonatal period and neonatal seizures lead to a propensity for epilepsy and long-term cognitive deficits. Here, we identify potential mechanisms that elucidate a critical role for AMPA receptors (AMPARs) in epileptogenesis during this critical period in the developing brain. In a rodent model of neonatal seizures, we have shown previously that administration of antagonists of the AMPARs during the 48 h after seizures prevents long-term increases in seizure susceptibility and seizure-induced neuronal injury. Hypoxia-induced seizures in postnatal day 10 rats induce rapid and reversible alterations in AMPAR signaling resembling changes implicated previously in models of synaptic potentiation in vitro. Hippocampal slices removed after hypoxic seizures exhibited potentiation of AMPAR-mediated synaptic currents, including an increase in the amplitude and frequency of spontaneous and miniature EPSCs as well as increased synaptic potency. This increased excitability was temporally associated with a rapid increase in phosphorylation at GluR1 S845/S831 and GluR2 S880 sites and increased activity of the protein kinases CaMKII (calcium/calmodulin-dependent protein kinase II), PKA, and PKC, which mediate the phosphorylation of these AMPAR subunits. Postseizure administration of AMPAR antagonists NBQX (2,3-dihydroxy-6-nitro-7-sulfonyl-benzo[f]quinoxaline), topiramate, or GYKI-53773 [(1)-1-(4-aminophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine] attenuated the AMPAR potentiation, phosphorylation, and kinase activation and prevented the concurrent increase in in vivo seizure susceptibility. Thus, the potentiation of AMPAR-containing synapses is a reversible, early step in epileptogenesis that offers a novel therapeutic target in the highly seizure-prone developing brain.

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    • "This seems different in epileptogenesis induced in rat pups, in which twice daily administration of NBQX (20 mg/kg) over 2 days inhibited development of late spontaneous seizures and mossy fiber sprouting induced by hypoxia-induced neonatal seizures (Lippmann-Bell et al., 2013). In a previous study, the same group reported that early alterations of AMPA receptors mediate synaptic potentiation induced by neonatal seizures (Rakhade et al., 2008). Perampanel is approved for treatment in adults with partial epilepsy , so that it will be important to investigate whether this noncompetitive AMPA receptor antagonist exerts similar effects than NBQX in the neonatal rat model, and whether this can be translated to attenuating the risk of epilepsy after early life seizures. "
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    ABSTRACT: The AMPA receptor subtype of glutamate receptors, which mediates fast synaptic excitation, is of primary importance in initiating epileptiform discharges, so that AMPA receptor antagonists exert anti-seizure activity in diverse animal models of partial and generalized seizures. Recently, the first AMPA receptor antagonist, perampanel, was approved for use as adjunctive therapy for the treatment of resistant partial seizures in patients. Interestingly, the competitive AMPA receptor antagonist NBQX has recently been reported to prevent development of spontaneous recurrent seizures (SRS) in a neonatal seizure model in rats, indicating the AMPA antagonists may exert also antiepileptogenic effects. This prompted us to evaluate competitive (NBQX) and noncompetitive (perampanel) AMPA receptor antagonists in an adult mouse model of mesial temporal lobe epilepsy. In this model, SRS develop after status epilepticus (SE) induced by intrahippocampal injection of kainate. Focal electrographic seizures in this model are resistant to several major antiepileptic drugs. In line with previous studies, phenytoin was not capable of blocking such seizures in the present experiments, while they were markedly suppressed by NBQX and perampanel. However, perampanel was less tolerable than NBQX in epileptic mice, so that only NBQX was subsequently tested for antiepileptogenic potential. When mice were treated over three days after kainate-induced SE with NBQX (20 mg/kg t.i.d.), no effect on development or frequency of seizures was found in comparison to vehicle controls. These results suggest that AMPA receptor antagonists, while being effective in suppressing resistant focal seizures, are not exerting antiepileptogenic effects in an adult mouse model of partial epilepsy. Copyright © 2015. Published by Elsevier Ltd.
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    • "What constitutes a complete ASD phenotype in the rodent (Yang et al., 2011)? Are the mechanisms of initiation (Rakhade et al., 2008, 2012; Zhou et al., 2011) and maintenance of ASD/ID similar? What is the role of SRS? Are certain strains genetically predisposed to be susceptible to long term consequences following ELS? "
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    ABSTRACT: Recent work in Exp Neurol by Lugo et al. (2014b) demonstrated chronic alterations in sociability, learning and memory following multiple early life seizures (ELSs) in a mouse model. This work adds to the growing body of evidence supporting the detrimental nature of ELSs on the developing brain to contribute to aspects of an autistic phenotype with intellectual disability. Review of the face validity of behavioral testing and the construct validity of the models used informs the predictive ability and thus the utility of these models to translate underlying molecular and cellular mechanisms into future human studies.
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    • "mRNA was described after seizures (Mudo et al., 1995), but TrkC does not seem to play a major role in sustaining hyperexcitability (Soren Leonard et al., 2012). This study shows that TrkB is transiently activated in the immature brain after an epileptogenic insult in a clinically relevant model of early life seizures (Rakhade et al., 2011), and converges with a stream of evidence supporting the hypothesis that epileptogenic insults activate some of the molecular mechanisms implicated in normal synaptic plasticity , learning and memory (Talos et al., 2012; Rakhade et al., 2008; He et al., 2010). The study also shows that CEP-701, a drug with an established clinical safety profile , attenuates HS-induced seizure susceptibility, likely via its inhibition of TrkB. "
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    ABSTRACT: Tropomyosin-related kinase receptor B (TrkB) activation has been implicated in epileptogenesis. We investigated hippocampal levels of phosphorylated TrkB (p-TrkB) and potential antiepileptogenic actions of the tyrosine kinase inhibitor, lestaurtinib (CEP-701) in postnatal day 10 (P10) rat pups following hypoxic seizures (HS). Hippocampal expression of p-TrkB over total TrkB protein levels were assessed by immunoblot at 6, 12, or 24 hours post-HS, and revealed a statistically significant and transient 1.5-fold increase in hippocampal p-TrkB 12 hours post-HS compared to littermate normoxic controls. To investigate the effects of CEP-701, pups were treated with 2 doses of CEP-701 intraperitoneally (i.p.), 3 mg/kg/dose, immediately after and 12 hours post-HS. P-TrkB levels and susceptibility to kainic acid (KA)-induced seizures at P14 were compared between post-HS CEP-701-treated pups, post-HS vehicle-treated pups and normoxic littermates. Post-treatment with CEP-701 reversed the increased TrkB phosphorylation to baseline normoxic levels and attenuated the HS-related enhanced susceptibility to KA-induced seizures at P14. Given its known clinical safety profile, CEP-701 is a promising clinically translatable therapy to prevent epileptogenesis in the immature brain.
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