We seek to ultimately understand 3 basic questions: (1) Do early-life seizures (ELS) trigger intellectual disability (ID) with an autistic phenotype? (2) What signaling programs triggered by ELS potentially underlie this phenotype? (3) What are the rational, long-term pharmacological treatments to improve the abnormalities in synaptic plasticity and the in vivo phenotype? Our preliminary studies provide electrophysiological, pharmacological and biochemical evidence to suggest that ELS induces a chronic phenotype similar to other genetic forms of ID and autism such as Fragile X (FRAX) with FMRP dysfunction and Tuberous Sclerosis (TSC) with mTOR dysfunction. We propose three specific aims, utilizing electrophysiological, biochemical, immuno-cytochemistry and behavioral studies. Studies will use adult rats following a single kainate-induced ELS at post-natal day (P) 7. These studies will further investigate the mechanisms underlying altered mGluR-LTD measured electrophysiologically and test the hypothesis that ELS leads to a phenotype similar to other genetic forms of autism. Comparisons will be made to age-matched saline injected controls.
Specific Aim 1 : Determine the mechanisms underlying enhanced mGluR-dependent LTD observed following ELS. This will test the hypothesis that mGluR-dependent LTD is altered following ELS similar to that mediated by genetically disrupted FMRP expression and can be modified pharmacologically in a similar fashion.
Specific Aim 2 : Characterize the signaling pathways associated with S6 kinase (SK1) hyperactivation following ELS. This will test the hypothesis that signaling pathways are altered following ELS in a similar fashion to that mediated by disrupted FMRP expression and hyperactive mTOR, as in FRAX and TSC, respectively.
Specific Aim 3 : Further characterize the behavioral and electrographic in vivo phenotype following ELS. This will test the hypothesis that behavioral modalities beyond abnormal fear conditioning are induced by ELS that are consistent with an autism-like phenotype. By determining the pharmacological modulators of enhanced LTD following ELS, we will determine if this alteration in plasticity shares key features with that associated with FRAX and TSC. The pharmacological interventions advanced in FRAX and TSC are mirrored by our studies proposed here. Our studies will inform whether other forms of ID and autism potentially may share their pharmacological sensitivity and determine other potential therapeutic targets. These studies will advance the novel hypothesis that FMRP dysfunction can be seen in ID and/or autism outside of FRAX. This could impact treatment strategies for all causes of ID and/or autism. Our findings will support our hypothesis that seizures, as an external environmental factor, directly influence the development of ID and/or an autistic phenotype. These hypotheses cannot be tested in a straightforward fashion in patients. The use of our novel animal model of ELS triggering ID with an autistic phenotype allows these elusive clinical questions to be addressed more directly.

Public Health Relevance

We seek to ultimately understand 3 basic questions: (1) Do early-life seizures (ELS) trigger intellectual disability (ID) with an autistic phenotype? (2) What signaling programs triggered by ELS potentially underlie this phenotype? (3) What are the rational, long-term pharmacological treatments to improve the abnormalities in synaptic plasticity and the in vivo phenotype? By determining the pharmacological modulators of enhanced LTD following ELS, we will determine if this alteration in plasticity shares key features with that associated with FRAX and TSC. The pharmacological interventions advanced in FRAX and TSC are mirrored by our studies proposed here. Our studies will inform whether other forms of ID and autism potentially may share their pharmacological sensitivity and determine other potential therapeutic targets. These studies will advance the novel hypothesis that FMRP dysfunction can be seen in ID and/or autism outside of FRAX. This could impact treatment strategies for all causes of ID and/or autism. Our findings will support our hypothesis that seizures, as an external environmental factor, directly influence the development of ID and/or an autistic phenotype. These hypotheses cannot be tested in a straightforward fashion in patients. The use of our novel animal model of ELS triggering ID with an autistic phenotype allows these elusive clinical questions to be addressed more directly.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS076577-02
Application #
8323875
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Mamounas, Laura
Project Start
2011-09-01
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$333,473
Indirect Cost
$114,723
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Goodell, Dayton J; Benke, Tim A; Bayer, K Ulrich (2016) Developmental restoration of LTP deficits in heterozygous CaMKIIα KO mice. J Neurophysiol 116:2140-2151
Barcomb, Kelsey; Hell, Johannes W; Benke, Tim A et al. (2016) The CaMKII/GluN2B Protein Interaction Maintains Synaptic Strength. J Biol Chem 291:16082-9
O'Leary, Heather; Bernard, Paul B; Castano, Anna M et al. (2016) Enhanced long term potentiation and decreased AMPA receptor desensitization in the acute period following a single kainate induced early life seizure. Neurobiol Dis 87:134-44
Bernard, Paul B; Castano, Anna M; Beitzel, Christy S et al. (2015) Behavioral changes following a single episode of early-life seizures support the latent development of an autistic phenotype. Epilepsy Behav 44:78-85
Bernard, Paul B; Benke, Tim A (2015) Early life seizures: evidence for chronic deficits linked to autism and intellectual disability across species and models. Exp Neurol 263:72-8
Moezi, Leila; Pirsalami, Fatema; Inaloo, Soroor (2015) Constipation enhances the propensity to seizure in pentylenetetrazole-induced seizure models of mice. Epilepsy Behav 44:200-6
Benke, Tim A (2014) What you seize is what you get: do we yet understand epilepsy in rett syndrome? Epilepsy Curr 14:283-5
Bernard, Paul B; Castano, Anna M; Bayer, K Ulrich et al. (2014) Necessary, but not sufficient: insights into the mechanisms of mGluR mediated long-term depression from a rat model of early life seizures. Neuropharmacology 84:1-12
Benke, Tim (2014) What the dentate gyrus and the millennial in your basement have in common. Epilepsy Curr 14:152-4
Benke, Tim (2014) Benchmark IV Progressing Nicely: Rational Pharmacotherapy May Address Cognitive Decline in Epilepsy. Epilepsy Curr 14:90-2

Showing the most recent 10 out of 14 publications