Logo image
Back
AMPA GluA1-flip targeted oligonucleotide therapy reduces neonatal seizures and hyperexcitability
Journal article   Open access   Peer reviewed

AMPA GluA1-flip targeted oligonucleotide therapy reduces neonatal seizures and hyperexcitability

Nicole M Lykens, David J Coughlin, Jyoti M Reddi, Gordon J Lutz and Melanie K Tallent
PloS one, v 12(2), pp e0171538-e0171538
2017
DOI: https://doi.org/10.1371/journal.pone.0171538
PMID: 28178321
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1371/journal.pone.0171538View
Published, Version of Record (VoR)CC BY V4.0,  Open

Abstract

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
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.

Metrics

14 Record Views
7 citations in Web of Science
6 citations in Scopus

Details

UN Sustainable Development Goals (SDGs)

This publication has contributed to the advancement of the following goals:

#3 Good Health and Well-Being

InCites Highlights

Data related to this publication, from InCites Benchmarking & Analytics tool:

Collaboration types
Domestic collaboration
Web of Science research areas
Neurosciences
Logo image