Effects of NMDA-R1 antisense oligodeoxynucleotide administration: behavioral and radioligand binding studies
Abstract
The effects of an antisense phosphodiester oligodeoxynucleotide (ODN) directed to the NR1 subunit of the NMDA receptor mRNA and of its corresponding sense ODN were investigated in mice. Treatment with the antisense ODN significantly increased the time mice spent in the open arms of an elevated maze while the total number of arm entries was unaltered. Furthermore, seizure latencies after the administration of an ED100 dose of NMDA (150 mg/kg) were significantly higher in antisense treated animals compared to vehicle controls. At the same time, treatment with NR1 antisense ODN significantly reduced the Bmax of [3H]CGS-19755 binding (2101 fmol/mg protein) compared to both vehicle (2787 fmol/mg protein) and sense (2832 +/- 39 fmol/mg protein) controls without any significant change in KD (33 nM). A corresponding reduction of [3H]CGP-39653 binding was also observed after treatment with NR1 antisense compared to both sense and vehicle controls. In contrast, neither antisense nor sense ODNs altered the proportion of high affinity glycine sites or the potency of glycine at either high or low affinity glycine binding sites to inhibit [3H]CGP-39653 binding. These results show that in vivo treatment with NR1 antisense ODNs to the NMDA receptor complex reduces antagonist binding at NMDA receptors and has pharmacological effects similar to those observed with some NMDA receptor antagonists. These results also suggest that treatment with antisense ODNs may provide another means to investigate allosteric modulation of receptor subtypes in vivo.
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Many of the transcripts affected by Rbfox1−/− splicing changes are associated with seizure disorders in humans or mice.
“many of which are associated with seizure disorders in humans or mice, such as the GABAA receptor subunit Gabrg2, Grin1, the voltage-gated sodium channel Scn8a (which encodes NaV1.6), and synaptosomal-associated protein 25 (Snap25)133–137”
From The neurogenetics of alternative splicing (2016) · cites this paper as [135]
Rbfox1−/− splicing changes affect transcripts encoding ion channels, neurotransmitter receptors, structural proteins and Ca2+ signalling molecules.
“However, these splicing changes affect transcripts encoding ion channels, neurotransmitter receptors, structural proteins and Ca2+ signalling molecules”
From The neurogenetics of alternative splicing (2016) · cites this paper as [135]
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Cabredo, M. M. D. L. (2006) · LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas)
- Authors
- Zapata, A., Capdevila, J. L., Tarrason, G., Adan, J., Martı́nez, J. M., Piulats, J., & Trullas, R.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- Merck, S.L.U. (Spain) (ES)
- Venue
- Brain Research
- Publisher
- Elsevier BV
- Published
- 1997-01
- Volume
- 745
- Issue
- 1-2
- Pages
- 114-120
- ISSN
- 0006-8993 (ISSN-L)
- OpenAlex
- W2055927905
- Cited by
- 34
- References
- 39
- Citations by year
- 2024: 1 · 2021: 1 · 2016: 1 · 2015: 1 · 2014: 1
- FWCI
- 1.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain Research (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- Grupo Ferrer Internacional, S.A
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- NMDA receptor, NR1 subunit, antisense oligodeoxynucleotides, gene silencing, seizure latency, NMDA-induced seizures, CGS 19755, antagonist binding, glycine site, allosteric modulation, NMDA receptor antagonists
- MeSH terms
- Animals, Behavior, Animal, Brain, Injections, Intraventricular, Male, Pipecolic Acids, Radioligand Assay, Seizures, Anti-Anxiety Agents, 2-Amino-5-phosphonovalerate, Receptors, N-Methyl-D-Aspartate, Oligonucleotides, Antisense, Receptors, Glycine, Excitatory Amino Acid Antagonists, Mice
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