Article

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

ABSTRACT

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.

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    • "The behavioral phenotype of the adult KA-ELS rat includes abnormal working memory, fear conditioning, socialization, and increased anxiety (Cornejo et al., 2007; Bernard et al., 2013; Castelhano et al., 2013; Cornejo et al., 2008; Moreira et al., 2011; Sayin et al., 2004). This behavior profile is thought to be representative of ASD and ID, and similar behavior profiles have been seen in other rodent models of early life seizures (Lugo et al., 2014; Lippman-Bell et al., 2013; Talos et al., 2012) and in genetic rodent models of ID with associated ASD (Bakker and Oostra, 2003; LaSalle and Yasui, 2009; Waltereit et al., 2011). Strides have been made in identifying the mechanisms that underlie deficits in learning and ASD phenotype in the adult KA-ELS rat; however, the developmental pathogenesis has not been clearly defined. "
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    • "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. "
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    • "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 "
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