Article ; Online: AMPA GluA1-flip targeted oligonucleotide therapy reduces neonatal seizures and hyperexcitability.
PloS one
2017 Volume 12, Issue 2, Page(s) e0171538
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. ... ...
| 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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| MeSH term(s) | Alternative Splicing ; Animals ; Animals, Newborn ; Base Sequence ; Cognition ; Disease Models, Animal ; Disease Susceptibility ; Female ; Hippocampus/metabolism ; Hippocampus/physiopathology ; Male ; Mice ; Motor Activity ; Oligonucleotides/administration & dosage ; Oligonucleotides/chemistry ; Pyramidal Cells/metabolism ; Receptors, AMPA/genetics ; Seizures/genetics ; Seizures/physiopathology ; Seizures/therapy ; Synaptic Transmission/genetics |
| Chemical Substances | Oligonucleotides ; Receptors, AMPA ; glutamate receptor ionotropic, AMPA 1 (TFZ3H25BS1) |
| Language | English |
| Publishing date | 2017-02-08 |
| Publishing country | United States |
| Document type | Journal Article |
| ISSN | 1932-6203 |
| ISSN (online) | 1932-6203 |
| DOI | 10.1371/journal.pone.0171538 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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