Local gene knockdown in the brain using viral-mediated RNA interference
Abstract
Conditional mutant techniques that allow spatial and temporal control over gene expression can be used to create mice with restricted genetic modifications. These mice serve as powerful disease models in which gene function in adult tissues can be specifically dissected. Current strategies for conditional genetic manipulation are inefficient, however, and often lack sufficient spatial control. Here we use viral-mediated RNA interference (RNAi) to generate a specific knockdown of Th, the gene encoding the dopamine synthesis enzyme tyrosine hydroxylase, within midbrain neurons of adult mice. This localized gene knockdown resulted in behavioral changes, including a motor performance deficit and reduced response to a psychostimulant. These results underscore the potential of using viral-mediated RNAi for the rapid production and testing of new genetic disease models. Similar strategies may be used in other model species, and may ultimately find applications in human gene therapy.
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Viral delivery is the most effective available way to transfect neurons.
“Viral delivery is the most effective available way to transfect neurons.13,24”
From Lipid Nanoparticle Delivery of siRNA to Silence Neuronal Gene Expression in the Brain (2013) · cites this paper as [24]
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“To underscore this point, it is noteworthy that there are numerous examples where acutely disrupting the function of a protein in mice has major consequences, but knockout of the same gene manifests as few, if any, discernable outcomes (Daude et al., 2012; De Souza et al., 2006; Hall et al., 2013; Hommel et al., 2003;…”
BackgroundProteasome inhibitor MG-132 induces dopaminergic degeneration in cell culture and animal models
Sun, F., Anantharam, V., Zhang, D., Latchoumycandane, C., Kanthasamy, A., & Kanthasamy, A. G. (2006) · NeuroToxicology · doi:10.1016/j.neuro.2006.06.006 · Cited by 107 · see citing works
Stimulation of entorhinal cortex-dentate gyrus circuitry is antidepressive
Yun, S., Reynolds, R. P., Petrof, I., White, A., Rivera, P. D., Segev, A., Gibson, A. D., Suarez, M., DeSalle, M. J., Ito, N., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0002-1 · Cited by 120 · see citing works
Son, H., Banasr, M., Choi, M., Chae, S. Y., Licznerski, P., Lee, B., Voleti, B., Li, N., Lepack, A., Fournier, N. M., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1201191109 · Cited by 103 · see citing works
“Behavioral testing was conducted 5 wk after viral infusion into dorsal DG, a time when AAV is fully expressed and stable (27) (Fig.”
MethodOrexin Signaling Via the Orexin 1 Receptor Mediates Operant Responding for Food Reinforcement
Sharf, R., Sarhan, M., Brayton, C. E., Guarnieri, D. J., Taylor, J. R., & Dileone, R. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.12.035 · Cited by 100 · see citing works
“To test this, we generated a viral vector (32,33) to reduce orexin gene expression in adult mice.”
BackgroundSelf-citationBrain-Targeted (Pro)renin Receptor Knockdown Attenuates Angiotensin II–Dependent Hypertension
Li, W., Peng, H., Cao, T., Sato, R., McDaniels, S. J., Kobori, H., Navar, L. G., & Feng, Y. (2012) · Hypertension · doi:10.1161/hypertensionaha.111.190108 · Cited by 100 · see citing works
Berton, O., Guigoni, C., Li, Q., Bioulac, B. H., Aubert, I., Gross, C. E., Dileone, R., Nestler, E. J., & Bézard, E. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.04.005 · Cited by 98 · see citing works
“Construction and packaging of AAV-ΔFosB-hrGFP and AAV-ΔJunD-hrGFP vectors has been described previously (32,33).”
MethodSelf-citationCdk5 Modulates Cocaine Reward, Motivation, and Striatal Neuron Excitability
Benavides, D. R., Quinn, J. J., Zhong, P., Hawasli, A. H., Dileone, R., Kansy, J. W., Olausson, P., Yan, Z., Taylor, J. R., & Bibb, J. A. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.4061-07.2007 · Cited by 97 · see citing works
“Generation of NAc-specific Cdk5 knock-out mice using rAAV Adeno-associated viral vectors were infused into the brain via stereotaxic surgical procedures as described previously (Hommel et al., 2003; Berton et al., 2006).”
MethodSelf-citationEngineering Mucosal RNA Interference in Vivo
Zhang, Y., Cristofaro, P. A., Silbermann, R. W., Pusch, O., Boden, D., Konkin, T., Hovanesian, V., Monfils, P. R., Resnick, M., Moss, S. F., et al. (2006) · Molecular Therapy · doi:10.1016/j.ymthe.2006.04.001 · Cited by 97 · see citing works
Innovative nanotechnologies for the delivery of oligonucleotides and siRNA
Toub, N., Malvy, C., Fattal, E., & Couvreur, P. (2006) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2006.07.093 · Cited by 96 · see citing works
Dillon, C. P., Sandy, P., Nencioni, A., Kissler, S., Rubinson, D. A., & Parijs, L. V. (2004) · Annual Review of Physiology · doi:10.1146/annurev.physiol.67.040403.130716 · Cited by 95 · see citing works
Rational targeting for prion therapeutics
Mallucci, G. R., & Collinge, J. (2004) · Nature reviews. Neuroscience · doi:10.1038/nrn1584 · Cited by 93 · see citing works
The Neuronal PAS Domain Protein 4 (Npas4) Is Required for New and Reactivated Fear Memories
Ploski, J. E., Monsey, M. S., Nguyen, T., Dileone, R., & Schafe, G. E. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023760 · Cited by 92 · see citing works
“Shorthairpin oligonucleotides designed to target Npas4 mRNA for degradation were annealed and cloned into SapI/XbaI sites of the AAV-GFP plasmid, a modified pCMV-MCS AAV vector [14].”
MethodSelf-citationAn epigenetic mechanism mediates developmental nicotine effects on neuronal structure and behavior
Jung, Y., Hsieh, L. S., Lee, A. M., Zhou, Z., Coman, D., Heath, C. J., Hyder, F., Mineur, Y. S., Yuan, Q., Goldman, D., et al. (2016) · Nature Neuroscience · doi:10.1038/nn.4315 · Cited by 90 · see citing works
Nie, H., Rewal, M., Gill, T. M., Dorit Ron, A., & Janak, P. H. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1016156108 · Cited by 90 · see citing works
Winstanley, C. A., Bachtell, R. K., Theobald, D. E. H., Laali, S., Green, T. A., Kumar, A., Chakravarty, S., Self, D. W., & Nestler, E. J. (2008) · Cerebral Cortex · doi:10.1093/cercor/bhn094 · Cited by 89 · see citing works
“See Hommel et al. (2003) for details of AAV preparation.”
Anastasio, N. C., Stutz, S. J., Fink, L. H. L., Swinford-Jackson, S. E., Sears, R. M., Dileone, R., Rice, K. C., Moeller, F. G., & Cunningham, K. A. (2015) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5b00094 · Cited by 88 · see citing works
Self-citationΔFosB in the nucleus accumbens is critical for reinforcing effects of sexual reward
Pitchers, K. K., Frohmader, K. S., Vialou, V., Mouzon, E., Nestler, E. J., Lehman, M. N., & Coolen, L. M. (2010) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2010.00621.x · Cited by 87 · see citing works
“The vectors produce no toxicity greater than control infusions alone (Winstanley et al. 2007; for details of AAV preparation, see Hommel et al. 2003).”
BackgroundDiscovery, biology and therapeutic potential of RNA interference, microRNA and antagomirs
Yang, M., & Mattes, J. E. (2007) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2007.08.004 · Cited by 87 · see citing works
Stratinaki, M., Varidaki, A., Mitsi, V., Ghose, S., Magida, J., Dias, C., Russo, S. J., Vialou, V., Caldarone, B. J., Tamminga, C. A., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1214696110 · Cited by 82 · see citing works
“AAV-Rgs4, AAV-GFP, and AAV-Cre were produced by using a triple transfection helper-free method in HEK cells and purified, as described (18, 37).”
MethodViggiano, D. (2008) · Behavioural Brain Research · doi:10.1016/j.bbr.2008.06.033 · Cited by 82 · see citing works
“TH blocker alpha-methyl-p-tyrosine [210] TH KO (dopamine-deficient) [98,100,127,192,236]”
BackgroundSalahpour, A., Medvedev, I. O., Beaulieu, J., Gainetdinov, R. R., & Caron, M. G. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.03.020 · Cited by 80 · see citing works
Adeno-Associated Virus Vectors for Short Hairpin RNA Expression
Grimm, D., Pandey, K., & Kay, M. A. (2005) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(04)92023-x · Cited by 79 · see citing works
“Similar to the first study by Hommel et al. (2003), the vectors were evaluated by using a mouse model of a human dominant neurodegenerative disease, here spinocerebellar ataxia type 1 (SCA1), and vector efficacy was demonstrated by showing reduction in target protein (ataxin-1) expression and by…”
Supernova: A Versatile Vector System for Single-Cell Labeling and Gene Function Studies in vivo
Luo, W., Mizuno, H., Iwata, R., Nakazawa, S., Yasuda, K., Itohara, S., & Iwasato, T. (2016) · Scientific Reports · doi:10.1038/srep35747 · Cited by 78 · see citing works
On the delivery of small interfering RNAs into mammalian cells
Sioud, M. (2005) · Expert Opinion on Drug Delivery · doi:10.1517/17425247.2.4.639 · Cited by 77 · see citing works
“AAVmediated delivery of antityrosine hydroxylase siRNAs into mouse midbrain neurons reduced the expression of its target protein [60].”
BackgroundRibosomal protein S6 kinase 1 signaling in prefrontal cortex controls depressive behavior
Dwyer, J. M., Maldonado-Avilés, J. G., Lepack, A. E., DiLeone, R. J., & Duman, R. S. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1505289112 · Cited by 76 · see citing works
“Constructs were confirmed by sequencing and packaged into AAV2 viral vectors using a triple-transfection, helper-free method as previously described (6).”
MethodSelf-citationThakker, D., Hoyer, D., & Cryan, J. (2006) · Pharmacology and Therapeutics · doi:10.1016/j.pharmthera.2005.08.006 · Cited by 66 · see citing works
Anastasio, N. C., Stutz, S. J., Fox, R. G., Sears, R. M., Emeson, R. B., Dileone, R., O’Neil, R. T., Fink, L. H. L., Li, D., Green, T. A., et al. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.199 · Cited by 75 · see citing works
“…downstream of the mU6pro region of a modified pAAV-MCS vector, pAAVshRNA, which was designed to coexpress hairpin RNAs, under the control of a mU6pro and an SV40 polyadenylation site, as well as eGFP controlled by an independent CMV promoter and hGH polyadenylation sequence (Hommel et al, 2003).”
InfluentialSelf-citationMultiple Actions of Spinophilin Regulate Mu Opioid Receptor Function
Charlton, J. J., Allen, P. B., Psifogeorgou, K., Chakravarty, S., Gomes, I., Neve, R. L., Devi, L. A., Greengard, P., Nestler, E. J., & Zachariou, V. (2008) · Neuron · doi:10.1016/j.neuron.2008.02.006 · Cited by 72 · see citing works
“AAV-spinophilin and AAV-GFP viruses were produced using a triple transfection helper free method in HEK cells and purified as described earlier (Hommel et al., 2003; Zachariou et al., 2006).”
Fremont, R., Tewari, A., & Khodakhah, K. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.06.004 · Cited by 73 · see citing works
“Knockdown of protein using shRNA delivered via AAV has been shown to occur on a similar timescale (Hommel et al., 2003).”
Spadaro, P. A., & Bredy, T. W. (2012) · Frontiers in Genetics · doi:10.3389/fgene.2012.00132 · Cited by 71 · see citing works
“Within the context of Parkinson’s disease, a neurodegenerative disease characterized by cognitive decline, Hommel et al. (2003) found that siRNA-mediated knockdown of Th, which is a gene responsible for the production of tyrosine hydroxylase and a key enzyme within the dopaminergic pathway,…”
BackgroundUlusoy, A., Şahin, G., Björklund, T., Aebischer, P., & Kirik, D. (2009) · Molecular Therapy · doi:10.1038/mt.2009.142 · Cited by 72 · see citing works
“5 Another study targeting mutant ataxin‐1 in a transgenic mouse model of spinocerebellar ataxia type 1 showed that rAAV2‐mediated shRNA silencing can lead to substantial decrease of human ataxin‐1 expression resulting in motor improvement and normalized cerebellar pathology.”
Anxiolytic function of the orexin 2/hypocretin A receptor in the basolateral amygdala
Arendt, D. H., Hassell, J. E., Li, H., Achua, J. K., Guarnieri, D. J., Dileone, R., Ronan, P. J., & Summers, C. H. (2013) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2013.10.010 · Cited by 71 · see citing works
“This vector was designed to coexpress hairpin RNAs, under the control of a mouse U6 promoter and an SV40 polyadenylation site, as well as EGFP controlled by an independent CMV promoter and hGH polyadenylation sequence (Hommel et al., 2003; Sharf et al., 2010).”
Self-citationRewal, M., Jurd, R., Gill, T. M., He, D.-Y., Ron, D., & Janak, P. H. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.3199-08.2009 · Cited by 71 · see citing works
“Therefore, to assess the relevance of the potentially alcohol-sensitive 4 GABAAR to alcohol’s actions, we used viral-mediated RNAi, which allows for region-specific reductions of target gene mRNA levels in adult animals (Hommel et al., 2003; Lasek et al., 2007), to determine the effect of reductions in 4 expression on…”
InfluentialKim, S.-J., Kim, J., Cho, H.-S., Lee, H., Kim, S. Y., Kim, S., Lee, S., & Chun, H. S. (2006) · Neuroreport · doi:10.1097/01.wnr.0000239951.14954.10 · Cited by 71 · see citing works
“In-vivo small interfering RNA experiments targeting TH expression in the SN showed behavioral changes, including a motor performance deficit and reduced response to psychostimulant [25].”
BackgroundMineur, Y. S., Mose, T. N., Blakeman, S., & Picciotto, M. R. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13769 · Cited by 71 · see citing works
“Two shRNAs targeting the mRNA encoding the α7 nAChR subunit were designed and ligated into pAAV-eGFP–shRNA as described previously (Hommel et al., 2003; Mineur et al., 2011).”
MethodMineur, Y. S., Cahuzac, E. L. M., Mose, T. N., Bentham, M. P., Plantenga, M. E., Thompson, D. C., & Picciotto, M. R. (2018) · Neuropsychopharmacology · doi:10.1038/s41386-018-0024-x · Cited by 71 · see citing works
“Virus production, purification, and infusion Adeno-associated virus 2 (AAV2) production was achieved by triple transfection of human embryonic kidney 239 cells with 135 μg each of pAAV-shRNA, pHelper and pAAV-RC plasmids using the standard calcium phosphate method as described previously [37, 38, 40].”
MethodHan, M.-H., Renthal, W. R., Ring, R. H., Rahman, Z. U., Psifogeorgou, K., Howland, D., Birnbaum, S. G., Young, K. H., Neve, R. L., Nestler, E. J., et al. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.08.041 · Cited by 70 · see citing works
“Floxed RGS4 mice were injected with either AAV-GFP or AAV-CreGFP into the NAc (41,42).”
RNA interference: from model organisms towards therapy for neural and neuromuscular disorders
Buckingham, S. D. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh224 · Cited by 70 · see citing works
Lasek, A. W., Janak, P. H., He, L., Whistler, J. L., & Heberlein, U. (2007) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2007.00303.x · Cited by 69 · see citing works
“…test the hypothesis that decreased MOR expression in the VTA will affect voluntary alcohol consumption, we used RNAi, a recently described method for specifically reducing target gene mRNA levels in the brain (Bahi et al. 2005; Hommel et al. 2003; Van den Haute et al. 2003; Xia et al. 2002).”
MethodLipophilic siRNAs mediate efficient gene silencing in oligodendrocytes with direct CNS delivery
Chen, Q., Butler, D., Querbes, W., Pandey, R. K., Ge, P., Maier, M. A., Zhang, L., Rajeev, K. G., Nechev, L. V., Koteliansky, V., et al. (2010) · Journal of Controlled Release · doi:10.1016/j.jconrel.2010.02.011 · Cited by 67 · see citing works
“Most of these studies used viral delivery of short hairpin RNA (shRNA) to achieve efficient knockdown of endogenous or reporter genes in the brain [12–16].”
BackgroundDopamine Regulation of Amygdala Inhibitory Circuits for Expression of Learned Fear
Kwon, O.-B., Lee, J. H., Kim, H. J., Lee, S., Lee, S., Jeong, M.-J., Kim, S.-J., Jo, H.-J., Ko, B., Chang, S., et al. (2015) · Neuron · doi:10.1016/j.neuron.2015.09.001 · Cited by 65 · see citing works
Gene therapy in clinical medicine
Sm, S. (2004) · Postgraduate medical journal · doi:10.1136/pgmj.2003.017764 · Cited by 49 · see citing works
Garza, J. C., Kim, C. S., Liu, J., Zhang, W., & Lu, X.-Y. (2008) · Journal of Endocrinology · doi:10.1677/joe-08-0009 · Cited by 65 · see citing works
“The robust EGFP expression in AAV-shRNA-transfected cells and healthy propagation of cells indicated that shRNAs were not toxic to the cells.”
Influentialde Solis, C. A., Ho, A., Holehonnur, R., & Ploski, J. E. (2016) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2016.00070 · Cited by 65 · see citing works
Viral-based modelling and correction of neurodegenerative diseases by RNA interference
Raoul, C., Barker, S. D., & Aebischer, P. (2005) · Gene Therapy · doi:10.1038/sj.gt.3302690 · Cited by 65 · see citing works
- Authors
- Hommel, J. D., Sears, R. M., Georgescu, D., Simmons, D. L., & DiLeone, R. J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- DiLeone, Ralph J
- Venue
- Nature Medicine
- Published
- 2003-11-23
- Volume
- 9
- Issue
- 12
- Pages
- 1539-1544
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2102238490
- Cited by
- 334
- References
- 37
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 6 · 2022: 3 · 2021: 2 · 2020: 5 · 2019: 5 · 2018: 13 · 2017: 10 · 2016: 10 · 2015: 17 · 2014: 15 · 2013: 16 · 2012: 19
- FWCI
- 11.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- tyrosine hydroxylase, dopamine synthesis, midbrain neurons, genetic disease models, gene therapy
- MeSH terms
- Dependovirus, Animals, Base Sequence, Behavior, Animal, Brain, DNA, Genetic Vectors, Humans, Male, Mice, Inbred C57BL, Tyrosine 3-Monooxygenase, Gene Expression, Mice, Knockout, Gene Targeting, RNA Interference, Mice
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