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

• Published in: PloS one Vol. 12; no. 2; p. e0171538
• Main Authors: Lykens, Nicole M, Coughlin, David J, Reddi, Jyoti M, Lutz, Gordon J, Tallent, Melanie K
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08.02.2017; Public Library of Science (PLoS)
• Subjects: Alternative Splicing; Animal cognition; Animal models; Animals; Animals, Newborn; Antagonists; Base Sequence; Biology and Life Sciences; Brain; Care and treatment; Cell receptors; Cognition; Development and progression; Disease Models, Animal; Disease Susceptibility; Drug dosages; Drugs; Epilepsy; Excitability; Excitatory postsynaptic potentials; Female; Genetic aspects; Health aspects; Hippocampus; Hippocampus - metabolism; Hippocampus - physiopathology; Innovations; Long-term depression; Long-term potentiation; Male; Medicine; Medicine and Health Sciences; Memory; Mice; Modulators; Molecular targeted therapy; Motor Activity; mRNA; Neonates; Neurological diseases; Neuromodulation; Neurons; Neurotoxicity; Neurotransmission; Newborn babies; Oligonucleotides; Oligonucleotides - administration & dosage; Oligonucleotides - chemistry; Pediatric diseases; Pharmacology; Physiology; Pyramidal Cells - metabolism; Receptors; Receptors, AMPA - genetics; Research and Analysis Methods; Rodents; Seizing; Seizures; Seizures (Medicine); Seizures - genetics; Seizures - physiopathology; Seizures - therapy; Studies; Synapses; Synaptic depression; Synaptic Transmission - genetics; Trends; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0171538

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.