A single episode of neonatal seizures permanently alters glutamatergic synapses

Cornejo, Brandon J.; Mesches, Michael H.; Coultrap, Steven J.; Browning, Michael; Benke, Tim A.

doi:10.1002/ana.21071

Cited by 136 publications

(159 citation statements)

References 82 publications

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“…Interestingly, sevoflurane is reported to cause epileptiform electroencephalographic activity [8], which may reflect a disruption in the normal balance of excitation and inhibition in the brain. The hyperexcitatory events raise significant concerns because they may potentially lead to subsequent cognitive impairments [21]. Because PV interneurons control the excitability of post-synaptic pyramidal neurons, it is possible that reduced PV expression results in diminished cortical inhibitory drive, which ultimately may lead to epileptiform electroencephalogram and consequent cognitive impairments.…”

Section: Discussionmentioning

confidence: 99%

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Repeated Neonatal Sevoflurane Exposure-Induced Developmental Delays of Parvalbumin Interneurons and Cognitive Impairments Are Reversed by Environmental Enrichment

Wang

Sun

et al. 2016

Mol Neurobiol

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Parvalbumin (PV) interneurons are critically involved in the cognitive processes. Based on prior investigations that environmental enrichment reverses impaired cognition after anesthetic exposure, we proposed that environmental enrichment protects PV interneurons and thereby improves sevoflurane-induced cognitive impairments. Six-day-old C57BL/6 male mice were exposed to 3 % sevoflurane or 30 % oxygen/air 2 h daily for 3 days from postnatal day 6 (P6) to P8. The mice were randomly allocated to an enriched environment for 2 h daily between P8 and P90 or a standard environment. Western blotting and immunofluorescence were used for determining PV expression in the prefrontal cortex and hippocampus. In another set of experiments, cognitive tests were assessed by the open field test (P41), Morris water maze test (P54-60), and fear conditioning tests (P42-43 and P89-90). Exposure of neonatal mice to sevoflurane resulted in a reduced freezing response in the contextual test at P43 but not P90. The PV expression in these mice was decreased at P9, P14, P28, and P42, but not at ≥P60. No colocalization of caspase-3 and 5-bromo-2-deoxyuridine or caspase-3 and PV was observed, suggesting that caspase-independent pathways may be involved in the mediation of sevoflurane-induced down-regulation of PV. The sevoflurane-exposed mice that were placed in an enriched environment exhibited normal behavior and had PV interneurons that did not differ from those in the control mice at P42-43. Neonatal sevoflurane exposure induces a reduced freezing response in the contextual test at P43 and developmental delays in PV interneurons in the prefrontal cortex and hippocampus. Placement of the sevoflurane-exposed mice in an enriched environment can prevent these abnormalities.

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Section: Discussionmentioning

confidence: 99%

“…Considering sevoflurane exposure can result in persistent cognitive impairments as assessed in the fear conditioning test [21], we performed this test at P42 to 43 and then again at P89 to 90. This test was examined in a black plastic chamber, with a stainless steel grid floor.…”

Section: Fear Conditioning Testmentioning

confidence: 99%

Repeated Neonatal Sevoflurane Exposure-Induced Developmental Delays of Parvalbumin Interneurons and Cognitive Impairments Are Reversed by Environmental Enrichment

Wang

Sun

et al. 2016

Mol Neurobiol

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“…These comorbidities, previously considered to be secondary to uncontrolled seizures or medication adverse effects, are now recognized as an integral part of the disorder, sometimes even preceding the seizures and attributable to an underlying disorder of neuronal networks (Brooks-Kayal et al 2013). Even a single seizure can alter neurodevelopment by modifying receptor expression and distribution in the absence of neuronal death, leading to cognitive and behavioral changes (Cornejo et al 2007). Understanding the pathophysiological link between these associated conditions and the epilepsies could have a major impact on the life of people living with epilepsy, and should be considered a research priority.…”

Section: Comorbiditiesmentioning

confidence: 99%

Seizures and Epilepsy: An Overview for Neuroscientists

Stafstrom

Carmant²

2015

Cold Spring Harbor Perspectives in Medicine

655

421

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Epilepsy is one of the most common and disabling neurologic conditions, yet we have an incomplete understanding of the detailed pathophysiology and, thus, treatment rationale for much of epilepsy. This article reviews the clinical aspects of seizures and epilepsy with the goal of providing neuroscientists an introduction to aspects that might be amenable to scientific investigation. Seizures and epilepsy are defined, diagnostic methods are reviewed, various clinical syndromes are discussed, and aspects of differential diagnosis, treatment, and prognosis are considered to enable neuroscientists to formulate basic and translational research questions.T his article provides an overview of seizures and epilepsy for neuroscientists. We focus on broad concepts, rather than clinical details, and raise questions related to mechanisms, epileptogenesis, and therapeutic approaches that might generate interest among basic researchers. Further information about differential diagnosis, drug doses, and clinical management are available from numerous resources (Engel and Pedley 2008;Duchowny et al. 2012;Engel 2013).We first define seizures and epilepsy and summarize their classification, pathophysiology, and genetics. Diagnostic methods are then considered, including the importance of an accurate historical description of an event suspected to be a seizure and the appropriate use of ancillary/confirmative tests, such as electroencephalogram (EEG), neuroimaging, and genetic studies. These modalities enable the clinician to differentiate epilepsy from numerous clinical conditions that mimic seizures, but have a nonepileptic pathophysiological basis. Examples of epilepsy syndromes are then described, selected based on their frequency in the population or because they embody scientific questions that warrant elucidation. Finally, we provide an overview of treatment options and prognosis, including a consideration of conditions that accompany epilepsy (comorbidities) and complicate the daily lives of people with epilepsy. Subsequent articles in this collection explore the scientific basis of many of the clinical concepts introduced here. DEFINITIONS AND EPIDEMIOLOGYA "seizure" is a paroxysmal alteration of neurologic function caused by the excessive, hyper-

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“…For example, such seizures modify the expression of glutamate receptors of various types (78-81), GABA receptors (82), and a number of additional important ion channels (83)(84)(85)(86). Notably, both the structural and molecular changes provoked by neonatal seizures might be persistent (87,88).…”

Section: The Neonatal Brain: Specific Vulnerabilities To the Effects mentioning

confidence: 99%

The Brain, Seizures and Epilepsy Throughout Life: Understanding a Moving Target

Baram

2012

Epilepsy Curr

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The Scope of the Problem The incidence of seizures and of epilepsy varies throughout life, peaking in neonates and children and increasing again after the age of 50 (1-4). In addition to the quantitative measure of the incidence of seizures, the type of seizures (and of epilepsy syndromes) varies with age: for example, febrile seizures take place in infants and children (1, 5-7), whereas the incidence of post-stroke epilepsy increases in adults compared with children (1,3,8). What is the basis of these age-dependent variations? What are the age-specific properties of the brain that contribute to the probability of seizure generation and to the nature of the resulting seizure?A second, reciprocal aspect of the interaction of the age of the brain and seizures involves the effects of a seizure on the structure and function of neurons and neuronal networks. Here, again, clinical evidence suggests that the consequences of a seizure might vary with age. For example, the consequences of status epilepticus (SE) in young children seem to depend on the inciting etiology (9, 10), and, in general, mortality and cognitive outcomes are more favorable than in the adult and elderly individual (11)(12)(13)(14). In contrast, status epilepticus in adult and aging individuals can have major detrimental effects on cognitive function and even survival (14-16). What is the basis of these age-dependent variations? What are the age-specific properties of the brain that modulate the effects of seizures on neuronal integrity and function?These questions are of paramount clinical importance because they should provide clues for developing age-specific diagnostic tools, prognostic models, and intervention strategies. Thus, while the answers to these questions are not fully elucidated, the questions provide a framework for discussing the salient elements of the evolving interaction between the brain and seizures throughout life.The following paragraphs highlight a few of the many facts that influence age-specific seizures and the age-specific consequences of seizures. Because most of the direct information about seizures throughout the life-span often derives from animal models, these are discussed. The author regrets that this overview is not comprehensive and likely omits a number of important publications. Nonetheless, this review serves to illustrate crucial features of the topic. Age-Specific Brain Properties Influence Seizures That Are Generated During Each AgeWhereas brain development from embryonic life to senescence is a continuum, here it is divided into four stages: the neonatal, childhood, adulthood, and aging epochs. The Neonatal Brain and Age-Specific Neonatal SeizuresThe neonatal brain is in a stage of rapid flux from both structural and functional perspectives. Neurons are still being born, circuits are being formed, and synapses are being established (17,18). Synaptic currents are often slower (19), neurotransmitters play trophic roles (20), and circuits are not fully mature (21). These facts predict that seizures may propag...

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A single episode of neonatal seizures permanently alters glutamatergic synapses

Abstract: These molecular consequences are consistent with the alterations in plasticity and memory caused by sNS at the synaptic level. Our data demonstrate the cognitive impact of sNS and associate memory deficits with specific alterations in glutamatergic synaptic function.

Cited by 136 publications

References 82 publications

Repeated Neonatal Sevoflurane Exposure-Induced Developmental Delays of Parvalbumin Interneurons and Cognitive Impairments Are Reversed by Environmental Enrichment

Repeated Neonatal Sevoflurane Exposure-Induced Developmental Delays of Parvalbumin Interneurons and Cognitive Impairments Are Reversed by Environmental Enrichment

Seizures and Epilepsy: An Overview for Neuroscientists

The Brain, Seizures and Epilepsy Throughout Life: Understanding a Moving Target

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