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. 2007 May 1;10(2):333–352. doi: 10.1111/j.1582-4934.2006.tb00403.x

Controlled and localized genetic manipulation in the brain

Rachel Aronoff 1, C C H Petersen 1,*
PMCID: PMC3933125  PMID: 16796803

Abstract

Brain structure and function are determined in part through experience and in part through our inherited genes. A powerful approach for unravelling the balance between activity-dependent neuronal plasticity and genetic programs is to directly manipulate the genome. Such molecular genetic studies have been greatly aided by the remarkable progress of large-scale genome sequencing efforts. Sophisticated mouse genetic manipulations allow targeted point-mutations, deletions and additions to the mouse genome. These can be regulated through inducible promoters expressing in genetically specified neuronal cell types. However, despite significant progress it remains difficult to target specific brain regions through transgenesis alone. Recent work suggests that transduction vectors, like lentiviruses and adeno-associated viruses, may provide suitable additional tools for localized and controlled genetic manipulation. Furthermore, studies with such vectors may aid the development of human genetic therapies for brain diseases.

Keywords: transgenic mice, gene targeting, gene regulation, transduction vectors, adeno-associated virus, lentivirus

References

  • 1.Mello CC, Kramer JM, Stinchcomb D, Ambros V. Efficient gene transfer in C. elegans: extrachromosomal maintenance and integration of transforming sequences. EMBO J. 1991;10:3959–70. doi: 10.1002/j.1460-2075.1991.tb04966.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Rubin GM, Spradling AC. Genetic transformation of Drosophila with transposable element vectors. Science. 1982;218:348–53. doi: 10.1126/science.6289436. [DOI] [PubMed] [Google Scholar]
  • 3.Nagy A, Gertsenstein M, Vintersten K, Behringer R. In: Manipulating the mouse embryo: a laboratory manual. 3rd. Nagy AEA, editor. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 2003. [Google Scholar]
  • 4.Auerbach AB. Production of functional transgenic mice by DNA pronuclear microinjection. Acta Biochim Pol. 2004;51:9–31. [PubMed] [Google Scholar]
  • 5.Feng G, Mellor RH, Bernstein M, Keller-Peck C, Nguyen QT, Wallace M, Nerbonne JM, Lichtman JW, Sanes JR. Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron. 2000;28:41–51. doi: 10.1016/s0896-6273(00)00084-2. [DOI] [PubMed] [Google Scholar]
  • 6.Vidal M, Morris R, Grosveld F, Spanopoulou E. Tissue-specific control elements of the Thy-1 gene. EMBO J. 1990;9:833–40. doi: 10.1002/j.1460-2075.1990.tb08180.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Caroni P. Overexpression of growth-associated proteins in the neurons of adult transgenic mice. J Neurosci Methods. 1997;71:3–9. doi: 10.1016/s0165-0270(96)00121-5. [DOI] [PubMed] [Google Scholar]
  • 8.Trachtenberg JT, Chen BE, Knott GW, Feng G, Sanes JR, Welker E, Svoboda K. Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex. Nature. 2002;420:788–94. doi: 10.1038/nature01273. [DOI] [PubMed] [Google Scholar]
  • 9.Grutzendler J, Kasthuri N, Gan WB. Long-term dendritic spine stability in the adult cortex. Nature. 2002;420:812–6. doi: 10.1038/nature01276. [DOI] [PubMed] [Google Scholar]
  • 10.Meyer AH, Katona I, Blatow M, Rozov A, Monyer H. In vivo labeling of parvalbumin-positive interneurons and analysis of electical coupling in identified neurons. J Neurosci. 2002;22:7055–64. doi: 10.1523/JNEUROSCI.22-16-07055.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Gong S, Zheng C, Doughty ML, Losos K, Didkovsky N, Schambra UB, Nowak NJ, Joyner A, Leblanc G, Hatten ME, Heintz N. A gene expression atlas of the central nervous system based on bacterial artifical chromosomes. Nature. 2003;425:917–25. doi: 10.1038/nature02033. [DOI] [PubMed] [Google Scholar]
  • 12.Zhang Y, Lu H, Bargmann CI. Pathogenic bacteria induce aversive olfactory learning in Caenorhabditis elegans. Nature. 2005;438:179–84. doi: 10.1038/nature04216. [DOI] [PubMed] [Google Scholar]
  • 13.Wu Q, Zhao Z, Shen P. Regulation of aversion to noxious food by Drosophila neuropeptide Y- and insulin-like systems. Nat Neurosci. 2005;8:1350–5. doi: 10.1038/nn1540. [DOI] [PubMed] [Google Scholar]
  • 14.Cordes SP. N-ethyl-N-nitrosourea mutagenesis: boarding the mouse mutant express. Microbiol Mol Biol Rev. 2005;69:426–39. doi: 10.1128/MMBR.69.3.426-439.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Dupuy AJ, Akagi K, Largaespada DA, Copeland NG, Jenkins NA. Mammalian mutagenesis using a highly mobile somatic Sleeping Beauty transposon system. Nature. 2005;436:221–6. doi: 10.1038/nature03691. [DOI] [PubMed] [Google Scholar]
  • 16.Carlson CM, Largaespada DA. Insertional mutagenesis in mice: new perspectives and tools. Nat Rev Genet. 2005;6:568–80. doi: 10.1038/nrg1638. [DOI] [PubMed] [Google Scholar]
  • 17.Kile BT, Hilton DJ. The art and design of genetic screens: mouse. Nat Rev Genet. 2005;6:557–67. doi: 10.1038/nrg1636. [DOI] [PubMed] [Google Scholar]
  • 18.Klysik J, Singer JD. Mice with the enhanced green fluorescent protein gene knocked in to chromosome 11 exhibit normal transmission ratios. Biochem Genet. 2005;43:321–33. doi: 10.1007/s10528-005-5223-6. [DOI] [PubMed] [Google Scholar]
  • 19.Capecchi MR. Altering the genome by homologous recombination. Science. 1989;244:1288–92. doi: 10.1126/science.2660260. [DOI] [PubMed] [Google Scholar]
  • 20.Giese KP, Fedorov NB, Filipkowski RK, Silva AJ. Autophosphorylation at Thr286 of the alpha calcium-calmodulin kinase II in LTP and learning. Science. 1998;279:870–3. doi: 10.1126/science.279.5352.870. [DOI] [PubMed] [Google Scholar]
  • 21.Silva AJ, Stevens CF, Tonegawa S, Wang Y. Deficient hippocampal long-term potentiation in alpha-calcium-calmodulin kinase II mutant mice. Science. 1992;257:201–6. doi: 10.1126/science.1378648. [DOI] [PubMed] [Google Scholar]
  • 22.Pettit DL, Perlman S, Malinow R. Potentiated transmission and prevention of further LTP by increased CaMKII activity in postsynaptic hippocampal slice neurons. Science. 1994;266:1881–5. doi: 10.1126/science.7997883. [DOI] [PubMed] [Google Scholar]
  • 23.Lledo PM, Hjelmstad GO, Mukherji S, Soderling TR, Malenka RC, Nicoll RA. Calcium/calmodulin-dependent kinase II and long-term potentiation enhance synaptic transmission by the same mechanism. Proc Natl Acad Sci USA. 1995;92:11175–9. doi: 10.1073/pnas.92.24.11175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Barria A, Malinow R. NMDA receptor subunit composition controls synaptic plasticity by regulating binding to CaMKII. Neuron. 2005;48:289–301. doi: 10.1016/j.neuron.2005.08.034. [DOI] [PubMed] [Google Scholar]
  • 25.Lisman JE. A mechanism for memory storage insensitive to molecular turnover: a bistable autophosphorylating kinase. Proc Natl Acad Sci USA. 1985;82:3055–7. doi: 10.1073/pnas.82.9.3055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Lisman J, Schulman H, Cline H. The molecular basis of CaMKII function in synaptic and behavioural memory. Nat Rev Neurosci. 2002;3:175–90. doi: 10.1038/nrn753. [DOI] [PubMed] [Google Scholar]
  • 27.Petersen CC, Malenka RC, Nicoll RA, Hopfield JJ. All-or-none potentiation at CA3-CA1 synapses. Proc Natl Acad Sci USA. 1998;95:4732–7. doi: 10.1073/pnas.95.8.4732. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.O'Connor DH, Wittenberg GM, Wang SS. Graded bidirectional synaptic plasticity is composed of switch-like unitary events. Proc Natl Acad Sci USA. 2005;102:9679–84. doi: 10.1073/pnas.0502332102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Bagal AA, Kao JP, Tang CM, Thompson SM. Longterm potentiation of exogenous glutamate responses at single dendritic spines. Proc Natl Acad Sci USA. 2005;102:14434–9. doi: 10.1073/pnas.0501956102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Hoess RH, Ziese M, Sternberg N. P1 site-specific recombination: nucleotide sequence of the recombining sites. Proc Natl Acad Sci USA. 1982;79:3398–402. doi: 10.1073/pnas.79.11.3398. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Hoess RH, Wierzbicki A, Abremski K. The role of the loxP spacer region in P1 site-specific recombination. Nucleic Acids Res. 1986;14:2287–300. doi: 10.1093/nar/14.5.2287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Sauer B, Henderson N. Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. Proc Natl Acad Sci USA. 1988;85:5166–70. doi: 10.1073/pnas.85.14.5166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Tsien JZ, Chen DF, Gerber D, Tom C, Mercer EH, Anderson DJ, Mayford M, Kandel ER, Tonegawa S. Subregion- and cell type-restricted gene knockout in mouse brain. Cell. 1996;87:1317–26. doi: 10.1016/s0092-8674(00)81826-7. [DOI] [PubMed] [Google Scholar]
  • 34.Tsien JZ, Huerta PT, Tonegawa S. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell. 1996;87:1327–38. doi: 10.1016/s0092-8674(00)81827-9. [DOI] [PubMed] [Google Scholar]
  • 35.Silver DP, Livingston DM. Self-excising retroviral vectors encoding the Cre recombinase overcome Cre-mediated cellular toxicity. Mol Cell. 2001;8:233–43. doi: 10.1016/s1097-2765(01)00295-7. [DOI] [PubMed] [Google Scholar]
  • 36.Metzger D, Chambon P. Site- and time-specific gene targeting in the mouse. Methods. 2001;24:71–80. doi: 10.1006/meth.2001.1159. [DOI] [PubMed] [Google Scholar]
  • 37.Leone DP, Genoud S, Atanasoski S, Grausenburger R, Berger P, Metzger D, Macklin WB, Chambon P, Suter U. Tamoxifen-inducible glia-specific Cre mice for somatic mutagenesis in oligodendrocytes and Schwann cells. Mol Cell Neurosci. 2003;22:430–40. doi: 10.1016/s1044-7431(03)00029-0. [DOI] [PubMed] [Google Scholar]
  • 38.Long Q, Shelton KD, Lindner J, Jones JR, Magnuson MA. Efficient DNA cassette exchange in mouse embryonic stem cells by staggered positive-negative selection. Genesis. 2004;39:256–62. doi: 10.1002/gene.20053. [DOI] [PubMed] [Google Scholar]
  • 39.Le Y, Gagneten S, Larson T, Santha E, Dobi A, v Agoston D, Sauer B. Far-upstream elements are dispensable for tissue-specific proenkephalin expression using a Cre-mediated knock-in strategy. J Neurochem. 2003;84:689–97. doi: 10.1046/j.1471-4159.2003.01573.x. [DOI] [PubMed] [Google Scholar]
  • 40.Wong ET, Kolman JL, Li YC, Mesner LD, Hillen W, Berens C, Wahl GM. Reproducible doxycycline-inducible transgene expression at specific loci generated by Cre-recombinase mediated cassette exchange. Nucleic Acids Res. 2005;33:e147. doi: 10.1093/nar/gni145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Gossen M, Bujard H. Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci USA. 1992;89:5547–51. doi: 10.1073/pnas.89.12.5547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Furth PA, St Onge L, Boger H, Gruss P, Gossen M, Kistner A, Bujard H, Hennighausen L. Temporal control of gene expression in transgenic mice by a tetracycline-responsive promoter. Proc Natl Acad Sci USA. 1994;91:9302–6. doi: 10.1073/pnas.91.20.9302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Urlinger S, Baron U, Thellmann M, Hasan MT, Bujard H, Hillen W. Exploring the sequence space for tetracycline-dependent transcriptional activators: novel mutations yield expanded range and sensitivity. Proc Natl Acad Sci USA. 2000;97:7963–8. doi: 10.1073/pnas.130192197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Mansuy IM, Winder DG, Moallem TM, Osman M, Mayford M, Hawkins RD, Kandel ER. Inducible and reversible gene expression with the rtTA system for the study of memory. Neuron. 1998;21:257–65. doi: 10.1016/s0896-6273(00)80533-4. [DOI] [PubMed] [Google Scholar]
  • 45.Michalon A, Koshibu K, Baumgartel K, Spirig DH, Mansuy IM. Inducible and neuron-specific gene expression in the adult mouse brain with the rtTA2S-M2 system. Genesis. 2005;43:205–12. doi: 10.1002/gene.20175. [DOI] [PubMed] [Google Scholar]
  • 46.Yu HM, Liu B, Chiu SY, Costantini F, Hsu W. Development of a unique system for spatiotemporal and lineage-specific gene expression in mice. Proc Natl Acad Sci USA. 2005;102:8615–20. doi: 10.1073/pnas.0500124102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Raineri I, Carlson EJ, Gacayan R, Carra S, Oberley TD, Huang TT, Epstein CJ. Strain-dependent high-level expression of a transgene for manganese superoxide dismutase is associated with growth retardation and decreased fertility. Free Radic Biol Med. 2001;31:1018–30. doi: 10.1016/s0891-5849(01)00686-4. [DOI] [PubMed] [Google Scholar]
  • 48.Everett RS, Evans HK, Hodges BL, Ding EY, Serra DM, Amalfitano A. Strain-specific rate of shutdown of CMV enhancer activity in murine liver confirmed by use of persistent [E1(-), E2b(-)] adenoviral vectors. Virology. 2004;325:96–105. doi: 10.1016/j.virol.2004.04.032. [DOI] [PubMed] [Google Scholar]
  • 49.Schumacher A, Koetsier PA, Hertz J, Doerfler W. Epigenetic and genotype-specific effects on the stability of de novo imposed methylation patterns in transgenic mice. J Biol Chem. 2000;275:37915–21. doi: 10.1074/jbc.M004839200. [DOI] [PubMed] [Google Scholar]
  • 50.Brooks SP, Pask T, Jones L, Dunnett SB. Behavioural profiles of inbred mouse strains used as transgenic backgrounds. II: cognitive tests. Genes Brain Behav. 2005;4:307–17. doi: 10.1111/j.1601-183X.2004.00109.x. [DOI] [PubMed] [Google Scholar]
  • 51.Kalueff AV, Tuohimaa P. Contrasting grooming phenotypes in three mouse strains markedly different in anxiety and activity (129S1, BALB/c and NMRI) Behav Brain Res. 2005;160:1–10. doi: 10.1016/j.bbr.2004.11.010. [DOI] [PubMed] [Google Scholar]
  • 52.Brooks SP, Pask T, Jones L, Dunnett SB. Behavioural profiles of inbred mouse strains used as transgenic backgrounds. I: motor tests. Genes Brain Behav. 2004;3:206–15. doi: 10.1111/j.1601-183X.2004.00072.x. [DOI] [PubMed] [Google Scholar]
  • 53.Raoul C, Abbas-Terki T, Bensadoun JC, Guillot S, Haase G, Szulc J, Henderson CE, Aebischer P. Lentiviral-mediated silencing of SOD1 through RNA interference retards disease onset and progression in a mouse model of ALS. Nat Med. 2005;11:423–8. doi: 10.1038/nm1207. [DOI] [PubMed] [Google Scholar]
  • 54.Genc S, Koroglu TF, Genc K. RNA interference in neuroscience. Brain Res Mol Brain Res. 2004;132:260–70. doi: 10.1016/j.molbrainres.2004.02.004. [DOI] [PubMed] [Google Scholar]
  • 55.Babcock AM, Standing D, Bullshields K, Schwartz E, Paden CM, Poulsen DJ. In vivo inhibition of hippocampal Ca2+/calmodulin-dependent protein kinase II by RNA interference. Mol Ther. 2005;11:899–905. doi: 10.1016/j.ymthe.2005.02.016. [DOI] [PubMed] [Google Scholar]
  • 56.Tiscornia G, Tergaonkar V, Galimi F, Verma IM. CRE recombinase-inducible RNA interference mediated by lentiviral vectors. Proc Natl Acad Sci USA. 2004;101:7347–51. doi: 10.1073/pnas.0402107101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Szulc J, Wizerowicz M, Sauvain MO, Trono D, Aebischer P. A versatile tool for conditional gene expression and knockdown. Nat Methods. 2006;3:109–16. doi: 10.1038/nmeth846. [DOI] [PubMed] [Google Scholar]
  • 58.Wolff JA, Budker V. The mechanism of naked DNA uptake and expression. Adv Genet. 2005;54:3–20. doi: 10.1016/S0065-2660(05)54001-X. [DOI] [PubMed] [Google Scholar]
  • 59.Rathenberg J, Nevian T, Witzemann V. High-efficiency transfection of individual neurons using modified electrophysiology techniques. J Neurosci Methods. 2003;126:91–8. doi: 10.1016/s0165-0270(03)00069-4. [DOI] [PubMed] [Google Scholar]
  • 60.Haas K, Sin WC, Javaherian A, Li Z, Cline HT. Single-cell electroporation for gene transfer in vivo. Neuron. 2001;29:583–91. doi: 10.1016/s0896-6273(01)00235-5. [DOI] [PubMed] [Google Scholar]
  • 61.Chen L, Woo SL. Complete and persistent phenotypic correction of phenylketonuria in mice by site-specific genome integration of murine phenylalanine hydroxylase cDNA. Proc Natl Acad Sci USA. 2005;102:15581–6. doi: 10.1073/pnas.0503877102. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  • 62.Shi N, Zhang Y, Zhu C, Boado RJ, Pardridge WM. Brain-specific expression of an exogenous gene after i.v. administration. Proc Natl Acad Sci USA. 2001;98:12754–9. doi: 10.1073/pnas.221450098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Verma IM, Weitzman MD. Gene therapy: twenty-first century medicine. Annu Rev Biochem. 2005;74:711–38. doi: 10.1146/annurev.biochem.74.050304.091637. [DOI] [PubMed] [Google Scholar]
  • 64.Merten OW, Geny-Fiamma C, Douar AM. Current issues in adeno-associated viral vector production. Gene Ther. 2005;12:S51–61. doi: 10.1038/sj.gt.3302615. [DOI] [PubMed] [Google Scholar]
  • 65.Li C, Samulski RJ. Serotype-specific replicating AAV helper constructs increase recombinant AAV type 2 vector production. Virology. 2005;335:10–21. doi: 10.1016/j.virol.2005.02.008. [DOI] [PubMed] [Google Scholar]
  • 66.Peden CS, Burger C, Muzyczka N, Mandel RJ. Circulating anti-wild-type adeno-associated virus type 2 (AAV2) antibodies inhibit recombinant AAV2 (rAAV2)-mediated, but not rAAV5-mediated, gene transfer in the brain. J Virol. 2004;78:6344–59. doi: 10.1128/JVI.78.12.6344-6359.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.McCarty DM, Young SM, Jr, Samulski R. Integration of adeno-associated virus (AAV) and recombinant AAV vectors. Annu Rev Genet. 2004;38:819–45. doi: 10.1146/annurev.genet.37.110801.143717. [DOI] [PubMed] [Google Scholar]
  • 68.Weitzman MD, Kyostio SR, Kotin RM, Owens RA. Adeno-associated virus (AAV) Rep proteins mediate complex formation between AAV DNA and its integration site in human DNA. Proc Natl Acad Sci USA. 1994;91:5808–12. doi: 10.1073/pnas.91.13.5808. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Gao G, Vandenberghe LH, Wilson JM. New recombinant serotypes of AAV vectors. Curr Gene Ther. 2005;5:285–97. doi: 10.2174/1566523054065057. [DOI] [PubMed] [Google Scholar]
  • 70.Walters RW, Yi SM, Keshavjee S, Brown KE, Welsh MJ, Chiorini JA, Zabner J. Binding of adeno-associated virus type 5 to 2,3-linked sialic acid is required for gene transfer. J Biol Chem. 2001;276:20610–6. doi: 10.1074/jbc.M101559200. [DOI] [PubMed] [Google Scholar]
  • 71.Xu J, Ma C, Bass C, Terwilliger EF. A combination of mutations enhances the neurotropism of AAV-2. Virology. 2005;341:203–14. doi: 10.1016/j.virol.2005.06.051. [DOI] [PubMed] [Google Scholar]
  • 72.Passini MA, Macauley SL, Huff MR, Taksir TV, Bu J, Wu IH, Piepenhagen PA, Dodge JC, Shihabuddin LS, O'Riordan CR, Schuchman EH, Stewart GR. AAV vector-mediated correction of brain pathology in a mouse model of Niemann-Pick A disease. Mol Ther. 2005;11:754–62. doi: 10.1016/j.ymthe.2005.01.011. [DOI] [PubMed] [Google Scholar]
  • 73.Chamberlin NL, Du B, de Lacalle S, Saper CB. Recombinant adeno-associated virus vector: use for transgene expression and anterograde tract tracing in the CNS. Brain Res. 1998;793:169–75. doi: 10.1016/s0006-8993(98)00169-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Kirik D, Rosenblad C, Bjorklund A, Mandel RJ. Long-term rAAV-mediated gene transfer of GDNF in the rat Parkinson's model: intrastriatal but not intranigral transduction promotes functional regeneration in the lesioned nigrostriatal system. J Neurosci. 2000;20:4686–700. doi: 10.1523/JNEUROSCI.20-12-04686.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Stettler DD, Yamahachi H, Li W, Denk W, Gilbert CD. Axons and synaptic boutons are highly dynamic in adult visual cortex. Neuron. 2006;49:877–87. doi: 10.1016/j.neuron.2006.02.018. [DOI] [PubMed] [Google Scholar]
  • 76.Kaspar BK, Vissel B, Bengoechea T, Crone S, Randolph-Moore L, Muller R, Brandon EP, Schaffer D, Verma IM, Lee KF, Heinemann SF, Gage FH. Adeno-associated virus effectively mediates conditional gene modification in the brain. Proc Natl Acad Sci USA. 2002;99:2320–5. doi: 10.1073/pnas.042678699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Scammell TE, Arrigoni E, Thompson MA, Ronan PJ, Saper CB, Greene RW. Focal deletion of the adenosine A1 receptor in adult mice using an adeno-associated viral vector. J Neurosci. 2003;23:5762–70. doi: 10.1523/JNEUROSCI.23-13-05762.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Rajji T, Chapman D, Eichenbaum H, Greene R. The role of CA3 hippocampal NMDA receptors in paired associate learning. J Neurosci. 2006;26:908–15. doi: 10.1523/JNEUROSCI.4194-05.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Acland GM, Aguirre GD, Bennett J, Aleman TS, Cideciyan AV, Bennicelli J, Dejneka NS, Pearce-Kelling SE, Maguire AM, Palczewski K, Hauswirth WW, Jacobson SG. Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in a canine model of childhood blindness. Mol Ther. 2005;12:1072–82. doi: 10.1016/j.ymthe.2005.08.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Sohocki MM, Daiger SP, Bowne SJ, Rodriquez JA, Northrup H, Heckenlively JR, Birch DG, Mintz-Hittner H, Ruiz RS, Lewis RA, Saperstein DA, Sullivan LS. Prevalence of mutations causing retinitis pigmentosa and other inherited retinopathies. Hum Mutat. 2001;17:42–51. doi: 10.1002/1098-1004(2001)17:1<42::AID-HUMU5>3.0.CO;2-K. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Li XG, Okada T, Kodera M, Nara Y, Takino N, Muramatsu C, Ikeguchi K, Urano F, Ichinose H, Metzger D, Chambon P, Nakano I, Ozawa K, Muramatsu SI. 2005. Viral-mediated temporally controlled dopamine production in a rat model of Parkinson disease Mol Ther. [DOI] [PubMed]
  • 82.Xia H, Mao Q, Eliason SL, Harper SQ, Martins IH, Orr HT, Paulson HL, Yang L, Kotin RM, Davidson BL. RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nat Med. 2004;10:816–20. doi: 10.1038/nm1076. [DOI] [PubMed] [Google Scholar]
  • 83.Naldini L, Blomer U, Gallay P, Ory D, Mulligan R, Gage FH, Verma IM, Trono D. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science. 1996;272:263–7. doi: 10.1126/science.272.5259.263. [DOI] [PubMed] [Google Scholar]
  • 84.Zufferey R, Dull T, Mandel RJ, Bukovsky A, Quiroz D, Naldini L, Trono D. Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery. J Virol. 1998;72:9873–80. doi: 10.1128/jvi.72.12.9873-9880.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.Deglon N, Tseng JL, Bensadoun JC, Zurn AD, Arsenijevic Y, Pereira de Almeida L, Zufferey R, Trono D, Aebischer P. Self-inactivating lentiviral vectors with enhanced transgene expression as potential gene transfer system in Parkinson's disease. Hum Gene Ther. 2000;11:179–90. doi: 10.1089/10430340050016256. [DOI] [PubMed] [Google Scholar]
  • 86.Jakobsson J, Ericson C, Jansson M, Bjork E, Lundberg C. Targeted transgene expression in rat brain using lentiviral vectors. J Neurosci Res. 2003;73:876–85. doi: 10.1002/jnr.10719. [DOI] [PubMed] [Google Scholar]
  • 87.Perletti G, Osti D, Marras E, Tettamanti G, de Eguileor M. Generation of VSV-G pseudotyped lentiviral particles in 293T cells. J Cell Mol Med. 2004;8:142–3. doi: 10.1111/j.1582-4934.2004.tb00269.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88.Dittgen T, Nimmerjahn A, Komai S, Licznerski P, Waters J, Margrie TW, Helmachen F, Denk W, Brecht M, Osten P. Lentivirus-based genetic manipulations of cortical neurons and their optical and electrophysiological monitoring in vivo. Proc Natl Acad Sci USA. 2004;101:18206–11. doi: 10.1073/pnas.0407976101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89.Aronoff R, Knott GW, Welker E, Zufferey R, Aebischer P, Petersen CC. Society for Neuroscience. Washington, DC: Soeiety for Neuroscience; 2004. Genetic manipulation of mouse barrel cortex using lentiviral vectors. San Diego, CA. [Google Scholar]
  • 90.Brecht M, Free MS, Garaschuk O, Helmchen F, Margrie TW, Svoboda K, Osten P. Novel approaches to monitor and manipulate single neurons in vivo. J Neurosci. 2004;24:9223–7. doi: 10.1523/JNEUROSCI.3344-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91.Maskos U, Molles BE, Pons S, Besson M, Guiard BP, Guilloux JP, Evrard A, Cazala P, Cormier A, Mameli-Engvall M, Dufour N, Cloez-Tayarani I, Bemelmans AP, Mallet J, Gardier AM, David V, Faure P, Granon S, Changeux JP. Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature. 2005;436:103–7. doi: 10.1038/nature03694. [DOI] [PubMed] [Google Scholar]
  • 92.Ahmed BY, Chakravarthy S, Eggers R, Hermens WT, Zhang JY, Niclou SP, Levelt C, Sablitzky F, Anderson PN, Lieberman AR, Verhaagen J. Efficient delivery of Cre-recombinase to neurons in vivo and stable transduction of neurons using adeno-associated and lentiviral vectors. BMC Neurosci. 2004;5:4. doi: 10.1186/1471-2202-5-4. : [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93.Kay MA, Glorioso JC, Naldini L. Viral vectors for gene therapy: the art of turning infectious agents into vehicles of therapeutics. Nat Med. 2001;7:33–40. doi: 10.1038/83324. [DOI] [PubMed] [Google Scholar]
  • 94.Palu G, Parolin C, Takeuchi Y, Pizzato M. Progress with retroviral gene vectors. Rev Med Virol. 2000;10:185–202. doi: 10.1002/(sici)1099-1654(200005/06)10:3<185::aid-rmv285>3.0.co;2-8. [DOI] [PubMed] [Google Scholar]
  • 95.Ghosh A, Yue Y, Duan D. Viral serotype and the transgene sequence influence overlapping adeno-associated viral (AAV) vector-mediated gene transfer in skeletal muscle. J Gene Med. 2006;8:298–305. doi: 10.1002/jgm.835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96.Mazarakis ND, Azzouz M, Rohll JB, Ellard FM, Wilkes FJ, Olsen AL, Carter EE, Barber RD, Baban DF, Kingsman SM, Kingsman AJ, O'Malley K, Mitrophanous KA. Rabies virus glycoprotein pseudotyping of lentiviral vectors enables retrograde axonal transport and access to the nervous system after peripheral delivery. Hum Mol Genet. 2001;10:2109–21. doi: 10.1093/hmg/10.19.2109. [DOI] [PubMed] [Google Scholar]
  • 97.Pfeifer A. Lentiviral transgenesis. Transgenic Res. 2004;13:513–22. doi: 10.1007/s11248-004-2735-5. [DOI] [PubMed] [Google Scholar]
  • 98.Lois C, Hong EJ, Pease S, Brown EJ, Baltimore D. Germline transmission and tissue-specific expression of transgenes delivered by lentiviral vectors. Science. 2002;295:868–72. doi: 10.1126/science.1067081. [DOI] [PubMed] [Google Scholar]
  • 99.Kronenberg S, Kleinschmidt JA, Bottcher B. Electron cryo-microscopy and image reconstruction of adeno-associated virus type 2 empty capsids. EMBO Rep. 2001;2:997–1002. doi: 10.1093/embo-reports/kve234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 100.Aronoff R, Linial M. Specificity of retroviral RNA packaging. J Virol. 1991;65:71–80. doi: 10.1128/jvi.65.1.71-80.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 101.Adam MA, Miller AD. Identification of a signal in a murine retrovirus that is sufficient for packaging of non-retroviral RNA into virions. J Virol. 1988;62:3802–6. doi: 10.1128/jvi.62.10.3802-3806.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 102.Sullenger BA, Cech TR. Tethering ribozymes to a retroviral packaging signal for destruction of viral RNA. Science. 1993;262:1566–9. doi: 10.1126/science.8248806. [DOI] [PubMed] [Google Scholar]
  • 103.Luban J, Goff SP. Mutational analysis of cis-acting packaging signals in human immunodeficiency virus type 1 RNA. J Virol. 1994;68:3784–93. doi: 10.1128/jvi.68.6.3784-3793.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 104.Nakamura A, Okazaki Y, Sugimoto J, Oda T, Jinno Y. Human endogenous retroviruses with transcriptional potential in the brain. J Hum Genet. 2003;48:575–81. doi: 10.1007/s10038-003-0081-8. [DOI] [PubMed] [Google Scholar]
  • 105.Sinibaldi-Vallebona P, Lavia P, Garaci E, Spadafora C. A role for endogenous reverse transcriptase in tumorigenesis and as a target in differentiating cancer therapy. Genes Chromosomes Cancer. 2006;45:1–10. doi: 10.1002/gcc.20266. [DOI] [PubMed] [Google Scholar]
  • 106.Muotri AR, Chu VT, Marchetto MC, Deng W, Moran JV, Gage FH. Somatic mosaicism in neuronal precursor cells mediated by L 1 retrotransposition. Nature. 2005;435:903–10. doi: 10.1038/nature03663. [DOI] [PubMed] [Google Scholar]
  • 107.Levine KL, Steiner B, Johnson K, Aronoff R, Quinton TJ, Linial ML. Unusual features of integrated cDNAs generated by infection with genome-free retroviruses. Mol Cell Biol. 1990;10:1891–900. doi: 10.1128/mcb.10.5.1891. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 108.Carlton MB, Colledge WH, Evans MJ. Generation of a pseudogene during retroviral infection. Mamm Genome. 1995;6:90–5. doi: 10.1007/BF00303250. [DOI] [PubMed] [Google Scholar]
  • 109.Zaiss AK, Son S, Chang LJ. RNA 3' readthrough of oncoretrovirus and lentivirus: implications for vector safety and efficacy. J Virol. 2002;76:7209–19. doi: 10.1128/JVI.76.14.7209-7219.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 110.Wu X, Burgess SM. Integration target site selection for retroviruses and transposable elements. Cell Mol Life Sci. 2004;61:2588–96. doi: 10.1007/s00018-004-4206-9. [DOI] [PubMed] [Google Scholar]
  • 111.Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, Lim A, Osborne CS, Pawliuk R, Morillon E, Sorensen R, Forster A, Fraser P, Cohen JI, De Saint Basile G, Alexander I, Wintergerst U, Frebourg T, Aurias A, Stoppa-Lyonnet D, Romana S, Radford-Weiss I, Gross F, Valensi F, Delabesse E, Macintyre E, Sigaux F, Soulier J, Leiva LE, Wissler M, Prinz C, Rabbitts TH, Le Deist F, Fischer A, Cavazzana-Calvo M. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science. 2003;302:415–9. doi: 10.1126/science.1088547. [DOI] [PubMed] [Google Scholar]
  • 112.Schmidt M, Glimm H, Wissler M, Hoffmann G, Olsson K, Sellers S, Carbonaro D, Tisdale JF, Leurs C, Hanenberg H, Dunbar CE, Kiem HP, Karlsson S, Kohn DB, Williams D, Von Kalle C. Efficient characterization of retro-, lenti-, and foamyvector-transduced cell populations by high-accuracy insertion site sequencing. Ann N Y Acad Sci. 2003;996:112–21. doi: 10.1111/j.1749-6632.2003.tb03239.x. [DOI] [PubMed] [Google Scholar]
  • 113.Muller HP, Varmus HE. DNA bending creates favored sites for retroviral integration: an explanation for preferred insertion sites in nucleosomes. EMBO J. 1994;13:4704–14. doi: 10.1002/j.1460-2075.1994.tb06794.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 114.Bushman FD. Tethering human immunodeficiency virus 1 integrase to a DNA site directs integration to nearby sequences. Proc Natl Acad Sci USA. 1994;91:9233–7. doi: 10.1073/pnas.91.20.9233. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 115.Tan W, Zhu K, Segal DJ, Barbas CF, 3rd, Chow SA. Fusion proteins consisting of human immunodeficiency virus type 1 integrase and the designed polydactyl zinc finger protein E2C direct integration of viral DNA into specific sites. J Virol. 2004;78:1301–13. doi: 10.1128/JVI.78.3.1301-1313.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 116.Kolb AF, Coates CJ, Kaminski JM, Summers JB, Miller AD, Segal DJ. Site-directed genome modification: nucleic acid and protein modules for targeted integration and gene correction. Trends Biotechnol. 2005;23:399–406. doi: 10.1016/j.tibtech.2005.06.005. [DOI] [PubMed] [Google Scholar]
  • 117.Lo Bianco C, Schneider BL, Bauer M, Sajadi A, Brice A, Iwatsubo T, Aebischer P. Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an alphasynuclein rat model of Parkinson's disease. Proc Natl Acad Sci USA. 2004;101:17510–5. doi: 10.1073/pnas.0405313101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 118.Zhou C, Wen ZX, Wang ZP, Guo X, Shi DM, Zuo HC, Xie ZP. Green fluorescent protein-labeled mapping of neural stem cells migrating towards damaged areas in the adult central nervous system. Cell Biol Int. 2003;27:943–5. doi: 10.1016/j.cellbi.2003.08.001. [DOI] [PubMed] [Google Scholar]
  • 119.Doroudchi MM, Liauw J, Heaton K, Zhen Z, Forsayeth JR. Adeno-associated virus-mediated gene transfer of human aromatic L-amino acid decarboxylase protects mixed striatal primary cultures from L-DOPA toxicity. J Neurochem. 2005;93:634–40. doi: 10.1111/j.1471-4159.2005.03048.x. [DOI] [PubMed] [Google Scholar]
  • 120.Zala D, Bensadoun J, Pereira de Almeida L, Leavitt BR, Gutekunst CA, Aebischer P, Hayden MR, Deglon N. Long-term lentiviral-mediated expression of ciliary neurotrophic factor in the striatum of Huntington's disease transgenic mice. Exp Neurol. 2004;185:26–35. doi: 10.1016/j.expneurol.2003.09.002. [DOI] [PubMed] [Google Scholar]
  • 121.Kells AP, Fong DM, Dragunow M, During MJ, Young D, Connor B. AAV-mediated gene delivery of BDNF or GDNF is neuroprotective in a model of Huntington disease. Mol Ther. 2004;9:682–8. doi: 10.1016/j.ymthe.2004.02.016. [DOI] [PubMed] [Google Scholar]
  • 122.Chen ZJ, Kren BT, Wong PY, Low WC, Steer CJ. Sleeping Beauty-mediated down-regulation of huntingtin expression by RNA interference. Biochem Biophys Res Commun. 2005;329:646–52. doi: 10.1016/j.bbrc.2005.02.024. [DOI] [PubMed] [Google Scholar]
  • 123.Deglon N, Aebischer P. Lentiviruses as vectors for CNS diseases. Curr Top Microbiol Immunol. 2002;261:191–209. doi: 10.1007/978-3-642-56114-6_10. [DOI] [PubMed] [Google Scholar]
  • 124.Richichi C, Lin EJ, Stefanin D, Colella D, Ravizza T, Grignaschi G, Veglianese P, Sperk G, During MJ, Vezzani A. Anticonvulsant and antiepileptogenic effects mediated by adeno-associated virus vector neuropeptide Y expression in the rat hippocampus. J Neurosci. 2004;24:3051–9. doi: 10.1523/JNEUROSCI.4056-03.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 125.Klugmann M, Wymond Symes C, Leichtlein CB, Klaussner BK, Dunning J, Fong D, Young D, During MJ. AAV-mediated hippocampal expression of short and long Homer 1 proteins differentially affect cognition and seizure activity in adult rats. Mol Cell Neurosci. 2005;28:347–60. doi: 10.1016/j.mcn.2004.10.002. [DOI] [PubMed] [Google Scholar]
  • 126.Malleret G, Haditsch U, Genoux D, Jones MW, Bliss TV, Vanhoose AM, Weitlauf C, Kandel ER, Winder DG, Mansuy IM. Inducible and reversible enhancement of learning, memory, and long-term potentiation by genetic inhibition of calcineurin. Cell. 2001;104:675–86. doi: 10.1016/s0092-8674(01)00264-1. [DOI] [PubMed] [Google Scholar]
  • 127.Tang YP, Shimizu E, Dube GR, Rampon C, Kerchner GA, Zhuo M, Liu G, Tsien JZ. Genetic enhancement of learning and memory in mice. Nature. 1999;401:63–9. doi: 10.1038/43432. [DOI] [PubMed] [Google Scholar]
  • 128.Farah MJ, Illes J, Cook–Deegan R, Gardner H, Kandel E, King P, Parens E, Sahakian B, Wolpe PR. Neurocognitive enhancement: what can we do and what should we do. Nat Rev Neurosci. 2004;5:421–5. doi: 10.1038/nrn1390. [DOI] [PubMed] [Google Scholar]

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