Hypoxic Seizures Research Articles

Hypoxic convulsions induced by adult respiratory distress syndrome in Covid-19 patient

Covid 19 is one of the major infections that primarily attacks the respiratory tract. The most common symptoms at onset of COVID-19 illness are temperature, cough, dyspnea, hemoptysis and diarrhea. In severe cases, patients may develop severe pneumonia - often billateral, acute respiratory distress syndrome (ARDS) and multi-organ failure including perimyocarditis. Hypoxic convulsions is a rare finding, however it is associated with very dangerous disease and poor prognosis. This current report presents severe Covid-19 patient with ARDS and severe hypoxia accompanied with hypoxic seizures after exclusion of meningoencephalitis and other possible etiologies for epileptic attack.

Phenobarbital does not worsen outcomes of neonatal hypoxia on hippocampal LTP on rats.

Neonatal hypoxia is a common cause of early-life seizures. Both hypoxia-induced seizures (HS), and the drugs used to treat them (e.g., phenobarbital, PB), have been reported to have long-lasting impacts on brain development. For example, in neonatal rodents, HS reduces hippocampal long-term potentiation (LTP), while PB exposure disrupts GABAergic synaptic maturation in the hippocampus. Prior studies have examined the impact of HS and drug treatment separately, but in the clinic, PB is unlikely to be given to neonates without seizures, and neonates with seizures are very likely to receive PB. To address this gap, we assessed the combined and separate impacts of neonatal HS and PB treatment on the development of hippocampal LTP. Male and female postnatal day (P)7 rat pups were subjected to graded global hypoxia (or normoxia as a control) and treated with either PB (or vehicle as a control). On P13-14 (P13+) or P29-37 (P29+), we recorded LTP of the Schaffer collaterals into CA1 pyramidal layer in acute hippocampal slices. We compared responses to theta burst stimulation (TBS) and tetanization induction protocols. Under the TBS induction protocol, female rats showed an LTP impairment caused by HS, which appeared only at P29+. This impairment was delayed compared to male rats. While LTP in HS males was impaired at P13+, it normalized by P29+. Under the tetanization protocol, hypoxia produced larger LTP in males compared to female rats. PB injection, under TBS, did not exacerbate the effects of hypoxia. However, with the tetanization protocol, PB - on the background of HS - compensated for these effects, returning LTP to control levels. These results point to different susceptibility to hypoxia as a function of sex and age, and a non-detrimental effect of PB when administered after hypoxic seizures.

THE ROLE OF TRANSCRANIAL ULTRASOUND IN THE EVALUATION OF HYPOXIC ISCHEMIC ENCEPHALOPATHY

Introduction: Hypoxic ischemic encephalopathy is a clinical term used to describe an abnormal neurobehavioral state that consists of a decreased level of consciousness with abnormalities in neuromotor tone. Any neonate, regardless of birth weight, size, or gestational age, who has a greater than average chance of morbidity or mortality, due to fetal, maternal or placental anomalies or an otherwise compromised pregnancy especially within the first 28 days of life is categorized as high-risk neonate. Cranial ultrasonography plays an important role in the diagnosis of significant lesions in infants presenting with hypoxic ischemic encephalopathy (HIE) and seizures and assessing severity, neurodevelopment outcome and neurological prognosis of these high-risk infants. In the neonate, many sutures and fontanelles are still open and these can be used as acoustic windows to look into the brain. Methodology: This was a hospital based descriptive observational study of 100 preterm and term babies with suspected brain injuries who were referred for cranial USG examination to the Radiodiagnosis Department of R.N.T. Medical College, Udaipur with hypoxic ischemic encephalopathy over a period of 18 months from June 2020 to November 2021. Results:The most common affected age group was 32-37weeks (51%). The abnormalities found on neurosonogram were germinal matrix hemorrhage, periventricular leucomalacia, cystic PVL, cerebral edema and ventriculomegaly. The most common abnormality was germinal matrix hemorrhage (17%) and subependymal hemorrhage (41%) was most common type. Isolated ventriculomegaly (53.8%) was more common than ventriculomegaly with hemorrhage (46.2%). Conclusion: Neurosonogram remains the accurate, rapid imaging modality of choice for detecting brain injuries in preterm infant. This technique is both sensitive and specific for detecting germinal matrix hemorrhage and periventricular leucomalacia. It is a useful modality to perform frequent follow-up scans. The advantages of neurosonogram are that it is easy to operate, non invasive, accurate, has lack of ionizing radiation, bed side availability for unstable infants, rapid diagnosis, wide availability, cost effectiveness and repeatability.

Lestaurtinib (CEP-701) modulates the effects of early life hypoxic seizures on cognitive and emotional behaviors in immature rats

Hypoxic encephalopathy of the newborn is a major cause of long-term neurological sequelae. We have previously shown that CEP-701 (lestaurtinib), a drug with an established safety profile in children, attenuates short-term hyperexcitability and tropomyosin-related kinase B (TrkB) receptor activation in a well-established rat model of early life hypoxic seizures (HS). Here, we investigated the potential long-term neuroprotective effects of a post-HS transient CEP-701 treatment. Following exposure to global hypoxia, 10 day old male Sprague–Dawley pups received CEP-701 or its vehicle and were sequentially subjected to the light–dark box test (LDT), forced swim test (FST), open field test (OFT), Morris water maze (MWM), and the modified active avoidance (MAAV) test between postnatal days 24 and 44 (P24-44). Spontaneous seizure activity was assessed by epidural cortical electroencephalography (EEG) between P50 and 100. Neuronal density and glial fibrillary acidic protein (GFAP) levels were evaluated on histological sections in the hippocampus, amygdala, and prefrontal cortex at P100. Vehicle-treated hypoxic rats exhibited significantly increased immobility in the FST compared with controls, and post-HS CEP-701 administration reversed this HS-induced depressive-like behavior (p < 0.05). In the MAAV test, CEP-701-treated hypoxic rats were slower at learning both context-cued and tone-signaled shock-avoidance behaviors (p < 0.05). All other behavioral outcomes were comparable, and no recurrent seizures, neuronal loss, or increase in GFAP levels were detected in any of the groups. We showed that early life HS predispose to long-lasting depressive-like behaviors, and that these are prevented by CEP-701, likely via TrkB modulation. Future mechanistically more specific studies will further investigate the potential role of TrkB signaling pathway modulation in achieving neuroprotection against neonatal HS, without causing neurodevelopmental adverse effects.

THUR 054 The heart holds answers the brain cannot to see

Neuronal ceroid lipofuscinosis (NCL) is a range of inherited lysosomal storage disorders. This case highlights the cardiac pathology associated with NCL and reports improved seizure control following correction of cardiac arrhythmias.A 26-year-old woman presented with episodes of altered awareness with head and eye deviation on a background of a progressive neurodegenerative disorder. She initially presented at 7 years of age with progressive retinal dystrophy. As a teenager she developed seizures with prominent myoclonus, psychosis, cognitive impairment and immobility. Her epilepsy was refractory to treatment and seizures had increased in frequency prior to admission.ECG demonstrated sinus bradycardia of 30bpm and episodes of 20 s sinus arrest. This was managed by the insertion of a pacemaker, resulting in a dramatic reduction in the frequency of her seizures. Investigation into the underlying disorder was revisited identifying vacuolated lymphocytes and homozygous CLN3 gene deletions. These findings are consistent with a diagnosis of juvenile NCL (Batten disease).This case demonstrates the importance of cardiac monitoring in investigating a change in seizure pattern. We hypothesise that the patient presented with reflex hypoxic seizures secondary to asystolic episodes. It also highlights the value of securing a diagnosis to enable appropriate cardiac screening in NCL patients.

The Role of Kainate Receptors in the Pathophysiology of Hypoxia-Induced Seizures in the Neonatal Mouse

Kainate receptors (KARs) are glutamate receptors with peak expression during late embryonic and early postnatal periods. Altered KAR-mediated neurotransmission and subunit expression are observed in several brain disorders, including epilepsy. Here, we examined the role of KARs in regulating seizures in neonatal C57BL/6 mice exposed to a hypoxic insult. We found that knockout of the GluK2 subunit, or blockade of KARs by UBP310 reduced seizure susceptibility during the period of reoxygenation. Following the hypoxic insult, we observed an increase in excitatory neurotransmission in hippocampal CA3 pyramidal cells, which was blocked by treatment with UBP310 prior to hypoxia. Similarly, we observed increased excitatory neurotransmission in CA3 pyramidal cells in an in vitro hippocampal slice model of hypoxic-ischemia. This increase was absent in slices from GluK2−/− mice and in slices treated with UBP310, suggesting that KARs regulate, at least in part, excitatory synaptic neurotransmission following in vivo hypoxia in neonatal mice. Data from these hypoxia models demonstrate that KARs, specifically those containing the GluK2 subunit, contribute to alterations in excitatory neurotransmission and seizure susceptibility, particularly during the reoxygenation period, in neonatal mice. Therapies targeting KARs may prove successful in treatment of neonates affected by hypoxic seizures.

Risks of asphyxia-related neonatal complications in offspring of mothers with type 1 or type 2 diabetes: the impact of maternal overweight and obesity

Aims/hypothesisWe aimed to compare the risks of severe asphyxia-related neonatal complications in the offspring of mothers with type 1 or type 2 diabetes, and to assess the impact of maternal overweight/obesity on these risks.MethodsThis was a population-based study of 1,343,751 live-born singleton infants in Sweden between 1997 and 2011, including 5941 and 711 infants of mothers with type 1 and type 2 diabetes, respectively. ORs with 95% CIs were calculated for low Apgar score (0–6) at 5 min after birth, hypoxic ischaemic encephalopathy and neonatal seizures.ResultsThe rates of a low Apgar score were 0.9%, 2.6% and 2.1% in the offspring of mothers without diabetes or with type 1 or type 2 diabetes, respectively. After controlling for maternal confounders (including BMI), the risk of a low Apgar score increased in the offspring of mothers with type 1 diabetes (OR 2.67, 95% CI 2.23, 3.20) but not in the offspring of mothers with type 2 diabetes (OR 1.25, 95% CI 0.66, 2.35). The ORs of hypoxic ischaemic encephalopathy or neonatal seizures were increased in the offspring of mothers with type 1 diabetes (OR 3.41, 95% CI 2.58, 4.49) and type 2 diabetes (OR 2.54, 95% CI 1.13, 5.69). Maternal overweight/obesity was a risk factor for asphyxia-related neonatal complications and low Apgar scores in the offspring of mothers with type 1 diabetes and mothers without diabetes.Conclusions/interpretationThe risks of a low Apgar score and severe asphyxia-related neonatal complications are increased in the offspring of mothers with type 1 or type 2 diabetes. Maternal overweight/obesity is an important contributing factor.

Neonatal seizures alter NMDA glutamate receptor GluN2A and 3A subunit expression and function in hippocampal CA1 neurons.

Neonatal seizures are commonly caused by hypoxic and/or ischemic injury during birth and can lead to long-term epilepsy and cognitive deficits. In a rodent hypoxic seizure (HS) model, we have previously demonstrated a critical role for seizure-induced enhancement of the AMPA subtype of glutamate receptor (GluA) in epileptogenesis and cognitive consequences, in part due to GluA maturational upregulation of expression. Similarly, as the expression and function of the N-Methyl-D-aspartate (NMDA) subtype of glutamate receptor (GluN) is also developmentally controlled, we examined how early life seizures during the critical period of synaptogenesis could modify GluN development and function. In a postnatal day (P)10 rat model of neonatal seizures, we found that seizures could alter GluN2/3 subunit composition of GluNs and physiological function of synaptic GluNs. In hippocampal slices removed from rats within 48–96 h following seizures, the amplitudes of synaptic GluN-mediated evoked excitatory postsynaptic currents (eEPSCs) were elevated in CA1 pyramidal neurons. Moreover, GluN eEPSCs showed a decreased sensitivity to GluN2B selective antagonists and decreased Mg2+ sensitivity at negative holding potentials, indicating a higher proportion of GluN2A and GluN3A subunit function, respectively. These physiological findings were accompanied by a concurrent increase in GluN2A phosphorylation and GluN3A protein. These results suggest that altered GluN function and expression could potentially contribute to future epileptogenesis following neonatal seizures, and may represent potential therapeutic targets for the blockade of future epileptogenesis in the developing brain.

Representativeness of enrollment into a perinatal research repository

Objective: To describe enrollment and compare demographic and clinical characteristics of neonates enrolled in the perinatal research repository (PRR) with eligible, but non-enrolled neonates.Methods: Characteristics from enrolled infants were compared with eligible, but non-enrolled infants using t-tests, Wilcoxon rank tests and χ2 tests.Results: Between 1 January 2010 and 31 December 2011, 622 infants admitted to the neonatal intensive care unit (NICU), born <37 weeks were screened for the PRR were eligible for enrollment. Of these, 233 enrolled in the study. There were no significant differences between enrolled and non-enrolled infants with regard to race, birth weight, gestational age and Apgar scores. Enrolled patients had a significantly longer length of stay [mean (standard deviation) = 55.0 (58.9) versus 38.0 (45.8) days; p < 0.01]. Mortality was significantly greater in the non-enrolled group (11.7 versus 3.0%; p < 0.01). Both groups had a similar total number of diagnoses [mean (standard deviation) = 5.7 (3.1) versus 5.8 (3.2)]; however, among survivors enrolled infants had slightly lower prevalence of hypoxic ischemic encephalopathy (0.0 versus 2.9%; p < 0.01) and seizures (1.8 versus 6.4%; p < 0.01). There were no significant differences in enrollment by prevalence of other morbidities.Conclusions: These results suggest that a specimen collecting repository can enroll a sufficiently representative sample of eligible patients.

Lestaurtinib (CEP-701) attenuates “second hit” kainic acid-induced seizures following early life hypoxic seizures

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 h post-HS, and revealed a statistically significant and transient 1.5-fold increase in hippocampal p-TrkB 12 h 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 h 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.

Gene Expression Profiling of a Hypoxic Seizure Model of Epilepsy Suggests a Role for mTOR and Wnt Signaling in Epileptogenesis

Microarray profiling was used to investigate gene expression in the hypoxic seizure model of acquired epilepsy in the rat, with the aim of characterizing functional pathways which are persistently activated or repressed during epileptogenesis. Hippocampal and cortical tissues were transcriptionally profiled over a one week period following an initial series of seizures induced by mild hypoxia at post-natal day 10 (P10), and the gene expression data was then analyzed with a focus on gene set enrichment analysis, an approach which emphasizes regulation of entire pathways rather than of individual genes. Animals were subjected to one of three conditions: a control with no hypoxia, hypoxic seizures, and hypoxic seizures followed by treatment with the AMPAR antagonist NBQX, a compound currently proposed to be a modulator of epileptogenesis. While temporal gene expression in the control samples was found to be consistent with known processes of neuronal maturation in the rat for the given time window, the hypoxic seizure response was found to be enriched for components of the PI3K/mTOR and Wnt signaling pathways, alongside gene sets representative of glutamatergic, synaptic and axonal processes, perhaps regulated as a downstream consequence of activation of these pathways. Wnt signaling components were also found enriched in the more specifically epileptogenic NBQX-responsive gene set. While activation of the mTOR pathway is consistent with its known role in epileptogenesis and strengthens the case for mTOR or PI3K pathway inhibitors as potential anti-epileptogenic drugs, investigation of the role of Wnt signaling and the effect of appropriate inhibitors might offer a parallel avenue of research toward anti-epileptogenic treatment of epilepsy.

A critical review of mTOR inhibitors and epilepsy: from basic science to clinical trials

Present medications for epilepsy have substantial limitations, such as medical intractability in many patients and lack of antiepileptogenic properties to prevent epilepsy. Drugs with novel mechanisms of action are needed to overcome these limitations. The mTOR signaling pathway has emerged as a possible therapeutic target for epilepsy. Preliminary clinical trials suggest that mTOR inhibitors reduce seizures in tuberous sclerosis complex (TSC) patients with intractable epilepsy. Furthermore, mTOR inhibitors have antiepileptogenic properties in preventing epilepsy in animal models of TSC. Besides TSC, accumulating preclinical data suggest that mTOR inhibitors may have antiseizure or antiepileptogenic actions in other types of epilepsy, including infantile spasms, neonatal hypoxic seizures, absence epilepsy and acquired temporal lobe epilepsy following brain injury, but these effects depend on a number of conditions. Future clinical and basic research is needed to establish whether mTOR inhibitors are an effective treatment for epilepsy.

Bumetanide enhances phenobarbital efficacy in a rat model of hypoxic neonatal seizures.

Neonatal seizures can be refractory to conventional anticonvulsants, and this may in part be due to a developmental increase in expression of the neuronal Na+-K+-2 Cl− cotransporter, NKCC1, and consequent paradoxical excitatory actions of GABAA receptors in the perinatal period. The most common cause of neonatal seizures is hypoxic encephalopathy, and here we show in an established model of neonatal hypoxia-induced seizures that the NKCC1 inhibitor, bumetanide, in combination with phenobarbital is significantly more effective than phenobarbital alone. A sensitive mass spectrometry assay revealed that bumetanide concentrations in serum and brain were dose-dependent, and the expression of NKCC1 protein transiently increased in cortex and hippocampus after hypoxic seizures. Importantly, the low doses of phenobarbital and bumetanide used in the study did not increase constitutive apoptosis, alone or in combination. Perforated patch clamp recordings from ex vivo hippocampal slices removed following seizures revealed that phenobarbital and bumetanide largely reversed seizure-induced changes in EGABA. Taken together, these data provide preclinical support for clinical trials of bumetanide in human neonates at risk for hypoxic encephalopathy and seizures.

Glutamate Receptor 1 Phosphorylation at Serine 831 and 845 Modulates Seizure Susceptibility and Hippocampal Hyperexcitability after Early Life Seizures

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.

Learning through Silence: Amping up Cognition after Neonatal Hypoxic Seizures through AMPA Receptor Inhibition

Learning through Silence: Amping up Cognition after Neonatal Hypoxic Seizures through AMPA Receptor Inhibition

Bullous emphysema with haemorrhage in a premature foal

SummaryA Warmblood foal was admitted at one day of age because of prematurity and seizures. Clinical and clinical pathology abnormalities were consistent with prematurity and suspected hypoxic seizures that responded to anti‐convulsive therapy. The foal stabilised after several days of intensive care but then developed an airway infection. Thoracic radiographs showed multiple cavitary lesions and ultrasound examination suggested intra‐cavital haemorrhage. The foal went on to develop septicaemia and was subjected to euthanasia. Post mortem examination revealed multiple bullous emphysema with haemorrhage. This disorder should be considered in the differential diagnosis of foals having air‐fluid filled cavities on thoracic radiographs.

Development of later life spontaneous seizures in a rodent model of hypoxia‐induced neonatal seizures

To study the development of epilepsy following hypoxia-induced neonatal seizures in Long-Evans rats and to establish the presence of spontaneous seizures in this model of early life seizures. Long-Evans rat pups were subjected to hypoxia-induced neonatal seizures at postnatal day 10 (P10). Epidural cortical electroencephalography (EEG) and hippocampal depth electrodes were used to detect the presence of seizures in later adulthood (> P60). In addition, subdermal wire electrode recordings were used to monitor age at onset and progression of seizures in the juvenile period, at intervals between P10 and P60. Timm staining was performed to evaluate mossy fiber sprouting in the hippocampi of P100 adult rats that had experienced neonatal seizures. In recordings made from adult rats (P60-180), the prevalence of epilepsy in cortical and hippocampal EEG recordings was 94.4% following early life hypoxic seizures. These spontaneous seizures were identified by characteristic spike and wave activity on EEG accompanied by behavioral arrest and facial automatisms (electroclinical seizures). Phenobarbital injection transiently abolished spontaneous seizures. EEG in the juvenile period (P10-60) showed that spontaneous seizures first occurred approximately 2 weeks after the initial episode of hypoxic seizures. Following this period, spontaneous seizure frequency and duration increased progressively with time. Furthermore, significantly increased sprouting of mossy fibers was observed in the CA3 pyramidal cell layer of the hippocampus in adult animals following hypoxia-induced neonatal seizures. Notably, Fluoro-Jade B staining confirmed that hypoxic seizures at P10 did not induce acute neuronal death. The rodent model of hypoxia-induced neonatal seizures leads to the development of epilepsy in later life, accompanied by increased mossy fiber sprouting. In addition, this model appears to exhibit a seizure-free latent period, following which there is a progressive increase in the frequency of electroclinical seizures.

The Choking Game and YouTube: A Dangerous Combination

To study postings of partial asphyxiation by adolescents on YouTube and to increase awareness of this dangerous activity as well as the value of YouTube as a research tool. Videos were searched on YouTube using many terms for recreational partial asphyxiation. Data were gathered on the participants and on the occurrence of hypoxic seizure. Sixty-five videos of the asphyxiation game were identified. Most (90%) participants were male. A variety of techniques were used. Hypoxic seizures were witnessed in 55% of videos, but occurred in 88% of videos that employed the "sleeper hold" technique. The videos were collectively viewed 173550 times on YouTube. YouTube has enabled millions of young people to watch videos of the "choking game" and other dangerous activities. Seeing videos may normalize the behavior among adolescents. Increased awareness of this activity may prevent some youths from participating and potentially harming themselves or others.

Repeated hypoxic episodes induce seizures and alter hippocampal network activities in mice

We examined intra-cranial electroencephalographic activity in a mouse model of global hypoxia in an attempt to explore the pathophysiology underlying hypoxic seizures. Mice between the ages of 22 and 41 days underwent repeated hypoxic challenges, and their behavioral and electroencephalographic activities were monitored continuously before, during and after the challenge. We found that the animals exhibited convulsive behaviors during the hypoxic challenge, but hippocampal/cortical electrographic ictal discharges were recognizable only after the repeated hypoxic challenge. When examined in hippocampal slices in vitro, the post-hypoxic hippocampal circuit was hyper-excitable and had a higher propensity than the control to generate repetitive excitatory field potentials. We postulate that an ictogenic process develops after an initial hypoxic challenge rendering an increase of seizure susceptibility to recurrent hypoxic insults.

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

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.