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: 6.75). 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.

Download full-text


Available from: Nikolaus Josef Sucher, Jul 18, 2015
1 Follower
  • Source
    • "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? "
    [Show abstract] [Hide abstract]
    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.
    Experimental Neurology 10/2014; 263. DOI:10.1016/j.expneurol.2014.09.018 · 4.62 Impact Factor
  • Source
    • "The results are expressed as the mean ± SE (n C 4 per group). Data were analyzed using t-tests, and significance was set at p \ 0.05 Neuromol Med using PILO, kainate, and LiCl-PILO drugs (Bracey et al. 2009; Condorelli et al. 1994; de Oliveira et al. 2011), or prolonged electrical stimulation or hypoxia-inductive SE (Brandt et al. 2003; Rakhade et al. 2008). In addition, the variable drug concentrations utilized or the different experimental time points used following the induction of SE should be taken into account. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Glutamate over-activation and the consequent neuronal excitotoxicity have been identified as crucial players in brain dysfunctions such as status epilepticus (SE). Owing to the central function of 2-amino-3-(hydroxyl-5-methylisoxazole-4-yl) propionic acid receptors (AMPARs) in fast excitatory neurotransmission, these receptors have been recognized to play a prominent role in the development and generation of epileptic seizure. This study was undertaken to investigate both the early changes that affect glutamatergic neurons in the rat cerebral cortex and hippocampus and the level and channel properties of AMPARs in response to SE. The results obtained after 3 h of pilocarpine (PILO)-induced SE showed a disorganization of glutamatergic neurons in the CA3 and a thinner neuronal cell layer in the dentate gyrus (DG) region as compared with controls. A significant increase in AMPAR GluA2 protein expression, a decrease in GluA1, GluA3, and GluA4 expression, and a reduction in the phosphorylation of Ser831-GluA1 and Ser880-GluA2 were also observed. In addition, we report a downregulation of R/G editing levels and of Flip splicing isoforms, with a prominent effect on the hippocampus of PILO-treated rats. Our results suggest the presence of an attenuation of AMPARs' post-synaptic excitatory response to glutamate after PILO treatment, thus conferring neuronal protection from the excitotoxic conditions observed in the SE. This study suggests a role for AMPARs in alterations of the glutamatergic pathway during the onset and early progression of epilepsy, thus indicating additional targets for potential therapeutic interventions.
    NeuroMolecular Medicine 03/2013; 15(2). DOI:10.1007/s12017-013-8221-6 · 3.89 Impact Factor
  • Source
    • "In models of synaptic potentiation, Ca 2+ influx following enhanced activity leads to activation of kinases like CaMKII and PKA, which in turn bind to the intracellular tails of the receptor at the PSD (Yoshimura et al., 2000; Lisman et al., 2002). CaMKII and other associated proteins have been proposed to act as slot proteins for AMPAR insertion (Lisman and Zhabotinsky, 2001), and previous reports have shown enhanced activity of CaMKII in the post-synaptic membrane following neonatal seizures in animal models (Cornejo et al., 2007; Rakhade et al., 2008). Recent data has led to the recognition of distinct process involved in exocytosis of the intracellular AMPARs to extra/perisynaptic sites, lateral diffusion to synaptic sites and retention at synapses via scaffolding proteins (Petrini et al., 2009; Opazo and Choquet, 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neonatal seizures can lead to later life epilepsy and neurobehavioral deficits, and there are no treatments to prevent these sequelae. We showed previously that hypoxia-induced seizures in a neonatal rat model induce rapid phosphorylation of serine-831 (S831) and Serine 845 (S845) sites of the AMPA receptor GluR1 subunit and later neuronal hyperexcitability and epilepsy, suggesting that seizure-induced posttranslational modifications may represent a novel therapeutic target. To unambiguously assess the contribution of these sites, we examined seizure susceptibility in wild-type mice versus transgenic knock-in mice with deficits in GluR1 S831 and S845 phosphorylation [GluR1 double-phosphomutant (GluR1 DPM) mice]. Phosphorylation of the GluR1 S831 and S845 sites was significantly increased in the hippocampus and cortex after a single episode of pentyleneterazol-induced seizures in postnatal day 7 (P7) wild-type mouse pups and that transgenic knock-in mice have a higher threshold and longer latencies to seizures. Like the rat, hypoxic seizures in P9 C57BL/6N wild-type mice resulted in transient increases in GluR1 S831 and GluR1 S845 phosphorylation in cortex and were associated with enhanced seizure susceptibility to later-life kainic-acid-induced seizures. In contrast, later-life seizure susceptibility after hypoxia-induced seizures was attenuated in GluR1 DPM mice, supporting a role for posttranslational modifications in seizure-induced network excitability. Finally, human hippocampal samples from neonatal seizure autopsy cases also showed an increase in GluR1 S831 and S845, supporting the validation of this potential therapeutic target in human tissue.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 12/2012; 32(49):17800-17812. DOI:10.1523/JNEUROSCI.6121-11.2012 · 6.75 Impact Factor
Show more