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Journal article
AMPA GluA1-flip targeted oligonucleotide therapy reduces neonatal seizures and hyperexcitability
PloS one, v 12(2), pp e0171538-e0171538
2017
PMCID: PMC5298276
PMID: 28178321
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Glutamate-activated α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-Rs) mediate the majority of excitatory neurotransmission in brain and thus are major drug targets for diseases associated with hyperexcitability or neurotoxicity. Due to the critical nature of AMPA-Rs in normal brain function, typical AMPA-R antagonists have deleterious effects on cognition and motor function, highlighting the need for more precise modulators. A dramatic increase in the flip isoform of alternatively spliced AMPA-R GluA1 subunits occurs post-seizure in humans and animal models. GluA1-flip produces higher gain AMPA channels than GluA1-flop, increasing network excitability and seizure susceptibility. Splice modulating oligonucleotides (SMOs) bind to pre-mRNA to influence alternative splicing, a strategy that can be exploited to develop more selective drugs across therapeutic areas. We developed a novel SMO, GR1, which potently and specifically decreased GluA1-flip expression throughout the brain of neonatal mice lasting at least 60 days after single intracerebroventricular injection. GR1 treatment reduced AMPA-R mediated excitatory postsynaptic currents at hippocampal CA1 synapses, without affecting long-term potentiation or long-term depression, cellular models of memory, or impairing GluA1-dependent cognition or motor function in mice. Importantly, GR1 demonstrated anti-seizure properties and reduced post-seizure hyperexcitability in neonatal mice, highlighting its drug candidate potential for treating epilepsies and other neurological diseases involving network hyperexcitability.
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Details
- Title
- AMPA GluA1-flip targeted oligonucleotide therapy reduces neonatal seizures and hyperexcitability
- Creators
- Nicole M Lykens - Drexel UniversityDavid J Coughlin - Widener UniversityJyoti M Reddi - Drexel UniversityGordon J Lutz - LifeSplice PharmaMelanie K Tallent - Drexel University
- Publication Details
- PloS one, v 12(2), pp e0171538-e0171538
- Publisher
- Public LIbrary of Science (PLOS)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000393712500049
- Scopus ID
- 2-s2.0-85012199053
- Other Identifier
- 991019169617904721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Neurosciences