A Knockdown Punch to the Brain
Posted February 03, 2010
RNA interference, a means of shutting down production of specific proteins, is starting to give intriguing results in a wide range of neuroscience disciplines. This November 2005 meeting of the Academy's RNAi Discussion Group spotlighted new strategies in this field, particularly efforts to block specific genes in mouse and rat models of human brain disease.
John Cryan described experiments in which small interfering RNAs (siRNAs) were infused into mouse brains to reduce expression of dopamine transporter (DAT), serotonin transporter (SERT), and glutamate receptor (mGluR7). Sergei Musatov showed that adeno-associated virus (AAV), a small DNA virus, can be a useful vector for continuously expressing a short hairpin RNA (shRNA) capable of silencing estrogen receptor alpha (ERα) in mouse brains. Richard Vallee silenced Lis1 by RNA interference during development of the fetal rat brain, recapitulating the failed cortical neuron migration seen in lissencephaly. Stefan Schlussman tested the idea that siRNAs directed against the mu opioid receptor mRNA could block heroin's action in vivo.
Use the tabs above to find a meeting report and multimedia from this event.
DNA-directed RNA Interference
The Promega Corporation's web site on this subject provides background on this topic.
This January 2006 "Brain Briefing" from the Society for Neuroscience offers a topical overview about RNAi for the neuroscience community.
Non-coding RNAs: Small Inhibitory-RNA (SiRNA, RNAi, microRNA)
A web page with links to animations on siRNAs, databases and commercial sources, and algorithms for siRNA design. Part of a workshop on bioinformatics from the National Center for Biotechnology Information (NCBI).
RNA Interference (RNAi) Reference List
Ambion publishes this technical bulletin with citations of recent papers in RNAi research.
Miller, V. M., H. L. Paulson & P. Gonzalez-Alegre. 2005. RNA interference in neuroscience: progress and challenges. Cell Mol. Neurobiol. 25: 1195-1207.
Sigmund, C. D. & R. L. Davisson. 2006. Targeting brain AT1 receptors by RNA interference. Hypertension 47: 145-146.
siRNA-Induced Widespread Gene Knockdown in the Adult Mouse Brain: Utility for Studying the Molecular Basis of Neuropsychiatric Disorders
Akaneya, Y., B. Jiang & T. Tsumoto. 2005. RNAi-induced gene silencing by local electroporation in targeting brain region. J. Neurophysiol. 93: 594-602.
Cryan, J. F. & A. Holmes. 2005. The ascent of mouse: advances in modelling human depression and anxiety. Nat. Rev. Drug Discov. 4: 775-790.
Fountaine, T. M., M. J. A. Wood & R. Wade-Martins. 2005. Delivering RNA interference to the mammalian brain. Curr. Gene Ther. 5: 399-410.
Thakker, D. R., D. Hoyer & J. F. Cryan. 2006. Interfering with the brain: use of RNA interference for understanding the pathophysiology of psychiatric and neurological disorders. Pharmacol. Ther. 109: 413-438.
Thakker, D. R., F. Natt, D. Husken et al. 2005. siRNA-mediated knockdown of the serotonin transporter in the adult mouse brain. Mol. Psychiatry 10:782-789, 714.
Thakker D. R., F. Natt F, D. Husken et al. 2004. Neurochemical and behavioral consequences of widespread gene knockdown in the adult mouse brain by using nonviral RNA interference. Proc. Natl. Acad. Sci. USA 101: 17270-17275.
Viral-Mediated RNA Interference in Neuroscience Research
Devidze, N., J. A. Mong, A. M. Jasnow et al. 2005. Sex and estrogenic effects on coexpression of mRNAs in single ventromedial hypothalamic neurons. Proc. Natl. Acad. Sci. USA 102: 14446-14451.
Simpson, E. R., M. Misso, K. N. Hewitt et al. 2005. Estrogen—the good, the bad, and the unexpected. Endocr. Rev. 26: 322-330.
Couse, J. F. & K. S. Korach. 1999. Estrogen receptor null mice: what have we learned and where will they lead us? Endocr. Rev. 20: 358-417. Full Text
Effects of LIS1 RNAi on Neural Stem Cell Polarization Division and Motility
Hatten, MD. 2005. LIS-less neurons don't even make it to the starting gate. J. Cell Biol. 170: 867-871.
Tsai, J. W., Y. Chen, A. R. Kriegstein & R. B. Vallee. 2005. LIS1 RNA interference blocks neural stem cell division, morphogenesis, and motility at multiple stages. J. Cell Biol. 170: 935-945.
Lovett-Racke, A. E., P. D. Cravens, A. R. Gocke et al. 2005. Therapeutic potential of small interfering RNA for central nervous system diseases. Arch. Neurol. 62: 1810-1813.
Effects of Local Infusion of Mu Opioid Receptor-Targeted Small Interfering RNA in the Adult Mouse Brain
Kreek, M. J., G. Bart, C. Lilly et al. 2005. Pharmacogenetics and human molecular genetics of opiate and cocaine addictions and their treatments. Pharmacol. Rev. 57: 1-26.
Pan, Y. X. 2005. Diversity and complexity of the mu opioid receptor gene: alternative pre-mRNA splicing and promoters. DNA Cell Biol. 24: 736-750.
Solecki, W., T. Krowka, M. Filip & R. Przewlocki. 2005. Role of opioidergic mechanisms and GABA uptake inhibition in the heroin-induced discriminative stimulus effects in rats. Pharmacol Rep. 57: 744-754.
Davidson, B. L., Ed. 2004. RNAi in the Brain: From Biology to Therapeutics. Society for Neuroscience, Washington, DC.
Society for Neuroscience
Fire, A. 2005. RNA Interference Technology: From Basic Science to Drug Development. Cambridge University Press, Cambridge, UK.
John Cryan, PhD
John Cryan is lecturer of pharmacology at the University College Cork School of Pharmacy. His current research interests include neuropsychopharmacological approaches for the treatment of depression, anxiety, cognitive dysfunction, and drug dependence. He also investigates the neural circuitry underlying such stress-related disorders, the role of metabotropic GABA and glutamate receptors in brain function, gene silencing in the brain in vivo, and the relationship between drug dependence and mood disorders. Finally, he works on developing novel rodent models of behavioral disorders with special emphasis on translational approaches.
Cryan received his PhD in pharmacology from the National University of Ireland. Prior to joining the University College Cork faculty, he spent four years at the Novartis Institutes for BioMedical Research in Basel, Switzerland, where his research group was responsible for the preclinical characterization of novel therapeutic targets and ligands for psychiatric disorders. In 2004 he received the Novartis Neuroscience Recognition Award, and in September 2005 he was honored with the Young Scientist Award at the biennial European Behavioral Pharmacology Society meeting.
Sergei Musatov, PhD
Sergei Musatov is a research scientist at Neurologix Inc. His research focuses on the development of novel gene therapy approaches for the treatment of neurodegenerative disorders.
Musatov received his PhD from the St. Petersburg State Medical University and N. N. Petrov Research Institute of Oncology. After moving to the United States, he worked as a research associate at The Rockefeller University and at Weill Medical College of Cornell University. The main projects he was involved in dealt with the mechanism of gene transfer by adeno-associated virus, the role of tumor suppressor PTEN, and the role of different estrogen receptors in behavior and neurodegenerative disorders.
Richard Vallee, PhD
Richard Vallee is a professor of pathology at Columbia University. He investigates motor proteins in axonal transport, brain developmental disease, and synaptic function.
Vallee received his PhD from Yale University. He received the 1996 NIH Merit Award, was selected as the AAAS Council Delegate in 1998, and served as the H. Arthur Smith Chair in Cancer Research from 1999 until 2001. He also serves as the associate editor of Cell Motility and the Cytoskeleton.
Stefan Schlussman, PhD
Stefan Schlussman is currently a research associate at The Rockefeller University. His research interests include individual vulnerability to the effects of drug abuse, behavioral neurobiology of addictive diseases, and neurochemical and behavioral correlates of androgenic anabolic steroid abuse.
Schlussman received his PhD in cell biology and anatomy from New York Medical College. Prior to joining The Rockefeller University, he performed research at the program in clinical pharmacology of the University of Medicine and Dentistry of New Jersey.
Beth Schachter, PhD, writes about life science, medicine and biotechnology. She is also a partner in Still Point Coaching & Consulting, a firm that helps life scientists with communications and career development skills.
Schachter has published in Nature Biotechnology, The New York Times, The Scientist, Bio IT-World, and the HMS Beagle, and has written for the Howard Hughes Medical Institute, The Society for Women's Health Research and The Institute of Medicine. She entered science communications as HMS Beagle's first scientific editor.
Schachter's benchtop-to-laptop transition took place in 1997. Before that she was a biomedical researcher. She had been an associate professor at Mount Sinai Medical School, and also had taught at Cold Spring Harbor Laboratories. She received her PhD in cell and molecular biology from University of Southern California, and received postdoctoral training at the University of California, San Francisco and Columbia University. She serves on the board of Science Writers in New York (SWINY), the local affiliate of National Association of Science Writers.