The Interaction between Early Life Epilepsy and Autistic-Like Behavioral Consequences: A Role for the Mammalian Target of Rapamycin (mTOR) Pathway

Department of Neurology, Children's Hospital, Boston, Massachusetts, United States of America.
PLoS ONE (Impact Factor: 3.23). 05/2012; 7(5):e35885. DOI: 10.1371/journal.pone.0035885
Source: PubMed


Early life seizures can result in chronic epilepsy, cognitive deficits and behavioral changes such as autism, and conversely epilepsy is common in autistic children. We hypothesized that during early brain development, seizures could alter regulators of synaptic development and underlie the interaction between epilepsy and autism. The mammalian Target of Rapamycin (mTOR) modulates protein translation and is dysregulated in Tuberous Sclerosis Complex, a disorder characterized by epilepsy and autism. We used a rodent model of acute hypoxia-induced neonatal seizures that results in long term increases in neuronal excitability, seizure susceptibility, and spontaneous seizures, to determine how seizures alter mTOR Complex 1 (mTORC1) signaling. We hypothesized that seizures occurring at a developmental stage coinciding with a critical period of synaptogenesis will activate mTORC1, contributing to epileptic networks and autistic-like behavior in later life. Here we show that in the rat, baseline mTORC1 activation peaks during the first three postnatal weeks, and induction of seizures at postnatal day 10 results in further transient activation of its downstream targets phospho-4E-BP1 (Thr37/46), phospho-p70S6K (Thr389) and phospho-S6 (Ser235/236), as well as rapid induction of activity-dependent upstream signaling molecules, including BDNF, phospho-Akt (Thr308) and phospho-ERK (Thr202/Tyr204). Furthermore, treatment with the mTORC1 inhibitor rapamycin immediately before and after seizures reversed early increases in glutamatergic neurotransmission and seizure susceptibility and attenuated later life epilepsy and autistic-like behavior. Together, these findings suggest that in the developing brain the mTORC1 signaling pathway is involved in epileptogenesis and altered social behavior, and that it may be a target for development of novel therapies that eliminate the progressive effects of neonatal seizures.

1 Follower
12 Reads
  • Source
    • "In the KA-P7 ELS model, anxiety was not altered in the elevated plus maze (EPM) or open field test (OFT) (Cornejo et al., 2008; Stafstrom et al., 1993). Others also reported no change in OFT or EPM after KA-P7 (Cognato et al., 2010, 2011) or OFT after GH (Lippman-Bell et al., 2013; Mikati et al., 2005; Talos et al., 2012). Similarly Lugo et al. reported no change in anxiety in the FL P7- 11 model, as measured using EPM; however hyperactivity was noted in the OFT. "
    [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 · 4.70 Impact Factor
  • Source
    • "Rodents submitted to this hypoxia model develop spontaneous seizures later in life, as well as mossy fiber sprouting and long-term behavioral alterations, including social deficits, memory impairments, and aggressiveness.91,92 Despite the lack of early neuronal injury,93 hypoxia-induced seizures promote hyperexcitability immediately after seizure recovery, facilitating long-term potentiation induction and generating longer ADs.94 Increased excitability persists in the adult hippocampus, suggesting that the epileptogenic effects of hypoxia are mediated by permanent effects on excitability and plasticity within hippocampal networks.94 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract: Epilepsy is a chronic neurological condition characterized by recurrent seizures that affects millions of people worldwide. Comprehension of the complex mechanisms underlying epileptogenesis and seizure generation in temporal lobe epilepsy and other forms of epilepsy cannot be fully acquired in clinical studies with humans. As a result, the use of appropriate animal models is essential. Some of these models replicate the natural history of symptomatic focal epilepsy with an initial epileptogenic insult, which is followed by an apparent latent period and by a subsequent period of chronic spontaneous seizures. Seizures are a combination of electrical and behavioral events that are able to induce chemical, molecular, and anatomic alterations. In this review, we summarize the most frequently used models of chronic epilepsy and models of acute seizures induced by chemoconvulsants, traumatic brain injury, and electrical or sound stimuli. Genetic models of absence seizures and models of seizures and status epilepticus in the immature brain were also examined. Major uses and limitations were highlighted, and neuropathological, behavioral, and neurophysiological similarities and differences between the model and the human equivalent were considered. The quest for seizure mechanisms can provide insights into overall brain functions and consciousness, and animal models of epilepsy will continue to promote the progress of both epilepsy and neurophysiology research.
    Neuropsychiatric Disease and Treatment 09/2014; 10:1693-1705. DOI:10.2147/NDT.S50371 · 1.74 Impact Factor
  • Source
    • "The effects of seizures on certain signaling pathways are also age-specific. Seizures can increase BDNF or FGF-2 in young animals, but this effect is more pronounced in older age groups (Kim et al., 2010; Kornblum et al., 1997; Talos et al., 2012b). It is therefore important to replicate specific findings to other seizure models as well as evaluate the overall functional impact of these changes to deduce whether these are impactful or compensated. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Seizures are very common in the early periods of life and are often associated with poor neurologic outcome in humans. Animal studies have provided evidence that early life seizures may disrupt neuronal differentiation and connectivity, signaling pathways, and the function of various neuronal networks. There is growing experimental evidence that many signaling pathways, like GABAA receptor signaling, the cellular physiology and differentiation, or the functional maturation of certain brain regions, including those involved in seizure control, mature differently in males and females. However, most experimental studies of early life seizures have not directly investigated the importance of sex on the consequences of early life seizures. The sexual dimorphism of the developing brain raises the question that early seizures could have distinct effects in immature females and males that are subjected to seizures. We will first discuss the evidence for sex-specific features of the developing brain that could be involved in modifying the susceptibility and consequences of early life seizures. We will then review how sex-related biological factors could modify the age-specific consequences of induced seizures in the immature animals. These include signaling pathways (e.g., GABAA receptors), steroid hormones, growth factors. Overall, there are very few studies that have specifically addressed seizure outcomes in developing animals as a function of sex. The available literature indicates that a variety of outcomes (histopathological, behavioral, molecular, epileptogenesis) may be affected in a sex-, age-, region- specific manner after seizures during development. Obtaining a better understanding for the gender-related mechanisms underlying epileptogenesis and seizure comorbidities will be necessary to develop better gender and age appropriate therapies.
    Neurobiology of Disease 05/2014; 72. DOI:10.1016/j.nbd.2014.05.021 · 5.08 Impact Factor
Show more

Preview (2 Sources)

12 Reads
Available from