Epilepsy is a disorder that involves far more than the occurrence of seizures, and seizures can cause neuronal network disturbances that result in a wide range of cognitive and behavioral impairment. To date, most work in the epilepsy field has centered on the mechanism or prevention of the ictal events themselves. The focus of my laboratory has been on the impact of early life seizures on brain development and epileptogenesis. The present proposal extends our work to determine whether these mechanisms also induce alterations that could lead to cognitive dysfunction manifesting in early life, such as autism. There is clinical evidence that early life seizures may be one of many precedents for autism, and epilepsy is common in patients with autism, suggesting an interaction between the two processes. Our prior and recent work suggests that at least in the immature brain, where baseline synaptic plasticity is enhanced, seizures appear to directly activate specific plasticity-associated signaling pathways. We hypothesize that seizure induced ?dysplasticity? may occlude normal plasticity involved in cognition, and induce abnormal patterns of synapse development similar to those observed in autism and other forms of neurodevelopmental delay. Using electrophysiological techniques, we will first examine the time course of seizure-induced interruption of normal synaptic plasticity in the immature brain. We will then determine whether specific activity-dependent signaling abnormalities known to be associated with autism occur de novo following seizures in the immature brain. Next, we will identify seizure induced mechanisms for their activation and test whether post-seizure intervention attenuates the altered structure and function of neuronal networks. Finally, we will determine whether similar alterations in signaling, regulatory, and synaptic proteins also are observed in human tissue following seizures and in cases of autism associated with neonatal or infantile seizures.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
1DP1OD003347-01
Application #
7341202
Study Section
Special Emphasis Panel (ZGM1-NDPA-G (P2))
Program Officer
Jones, Warren
Project Start
2007-09-30
Project End
2012-07-31
Budget Start
2007-09-30
Budget End
2008-07-31
Support Year
1
Fiscal Year
2007
Total Cost
$845,000
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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Sun, Hongyu; Juul, Halvor M; Jensen, Frances E (2016) Models of hypoxia and ischemia-induced seizures. J Neurosci Methods 260:252-60
Lechpammer, Mirna; Wintermark, Pia; Merry, Katherine M et al. (2016) Dysregulation of FMRP/mTOR Signaling Cascade in Hypoxic-Ischemic Injury of Premature Human Brain. J Child Neurol 31:426-32
Zhou, Chengwen; Sun, Hongyu; Klein, Peter M et al. (2015) Neonatal seizures alter NMDA glutamate receptor GluN2A and 3A subunit expression and function in hippocampal CA1 neurons. Front Cell Neurosci 9:362
Jantzie, Lauren L; Hu, Melody Y; Park, Hyun-Kyung et al. (2015) Chloride cotransporter NKCC1 inhibitor bumetanide protects against white matter injury in a rodent model of periventricular leukomalacia. Pediatr Res 77:554-62
Jantzie, Lauren L; Talos, Delia M; Jackson, Michele C et al. (2015) Developmental expression of N-methyl-D-aspartate (NMDA) receptor subunits in human white and gray matter: potential mechanism of increased vulnerability in the immature brain. Cereb Cortex 25:482-95
Loddenkemper, Tobias; Talos, Delia M; Cleary, Ryan T et al. (2014) Subunit composition of glutamate and gamma-aminobutyric acid receptors in status epilepticus. Epilepsy Res 108:605-15
Brownstein, Catherine A; Beggs, Alan H; Homer, Nils et al. (2014) An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge. Genome Biol 15:R53
Obeid, Makram; Rosenberg, Evan C; Klein, Peter M et al. (2014) Lestaurtinib (CEP-701) attenuates ""second hit"" kainic acid-induced seizures following early life hypoxic seizures. Epilepsy Res 108:806-10
Cleary, Ryan T; Sun, Hongyu; Huynh, Thanhthao et al. (2013) Bumetanide enhances phenobarbital efficacy in a rat model of hypoxic neonatal seizures. PLoS One 8:e57148

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