In Utero Electroporation as a Tool For Genetic Manipulation In Vivo to Study Psychiatric Disorders: From Genes to Circuits and Behaviors
Abstract
Many genetic risk factors for major mental disorders have key roles in brain development. Thus, exploring the roles for these genetic factors for brain development at the molecular, cellular, and neuronal circuit level is crucial for discovering how genetic disturbances affect high brain functions, which ultimately lead to disease pathologies. However, it is a tremendously difficult task, given that most mental disorders have genetic complexities in which many genetic risk factors have multiple roles in different cell types and brain regions over a time-course dependent manner. Furthermore, some genetic risk factors are likely to act epistatically in common molecular pathways. For this reason, a technique for spatial and temporal manipulation of multiple genes is necessary for understanding how genetic disturbances contribute to disease etiology. Here, the authors will review the said technique, in utero electroporation, which investigates the molecular disease pathways in rodent models for major mental disorders. This technique is also useful to examine the effect of genetic risks at the behavioral level. Furthermore, the authors will discuss the recent progress of this technology, such as inducible and cell type-specific targeting, as well as nonepisomal genetic manipulation, which provide further availability of this technique for research on major mental disorders.
Get full access to this article
View all access and purchase options for this article.
References
Bai J, Ramos RL, Ackman JB, Thomas AM, Lee RV, LoTurco JJ. 2003. RNAi reveals doublecortin is required for radial migration in rat neocortex. Nat Neurosci 6:1277–83.
Bai J, Ramos RL, Paramasivam M, Siddiqi F, Ackman JB, LoTurco JJ. 2008. The role of DCX and LIS1 in migration through the lateral cortical stream of developing forebrain. Dev Neurosci 30:144–56.
Bill BR, Geschwind DH. 2009. Genetic advances in autism: heterogeneity and convergence on shared pathways. Curr Opin Genet Dev 19:271–8.
Borrell V, Yoshimura Y, Callaway EM. 2005. Targeted gene delivery to telencephalic inhibitory neurons by directional in utero electroporation. J Neurosci Methods 143:151–8.
Cetin A, Komai S, Eliava M, Seeburg PH, Osten P. 2006. Stereotaxic gene delivery in the rodent brain. Nat Protoc 1: 3166–73.
Chen J, Lipska BK, Weinberger DR. 2006. Genetic mouse models of schizophrenia: from hypothesis-based to susceptibility gene-based models. Biol Psychiatry 59:1180–8.
Corbo JC, Deuel TA, Long JM, LaPorte P, Tsai E, Wynshaw-Boris A, and others. 2002. Doublecortin is required in mice for lamination of the hippocampus but not the neocortex. J Neurosci 22:7548–57.
Davidson BL, Breakefield XO. 2003. Viral vectors for gene delivery to the nervous system. Nat Rev Neurosci 4:353–64.
Ding S, Wu X, Li G, Han M, Zhuang Y, Xu T. 2005. Efficient transposition of the piggyBac (PB) transposon in mammalian cells and mice. Cell 122:473–83.
Fukuchi-Shimogori T, Grove EA. 2001. Neocortex patterning by the secreted signaling molecule FGF8. Science 294:1071–4.
Gottesman II, Gould TD. 2003. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 160:636–45.
Harrison PJ, Weinberger DR. 2005. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 10:40–68.
Ishizuka K, Kamiya A, Oh CE, Kanki H, Seshadri S, Robinson FJ, and others. 2011. A DISC1-dependent switch from neuronal proliferation to migration in the developing cortex. Nature, in press.
Jaaro-Peled H, Hayashi-Takagi A, Seshadri S, Kamiya A, Brandon NJ, Sawa A. 2009. Neurodevelopmental mechanisms of schizophrenia: understanding disturbed postnatal brain maturation through neuregulin-1-ErbB4 and DISC1. Trends Neurosci 32:485–95.
Kamiya A. 2009. Animal models for schizophrenia via in utero gene transfer: understanding roles for genetic susceptibility factors in brain development. Prog Brain Res 179:9–15.
Kamiya A, Kubo K, Tomoda T, Takaki M, Youn R, Ozeki Y, and others. 2005. A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol 7:1167–78.
Kamiya A, Tan PL, Kubo K, Engelhard C, Ishizuka K, Kubo A, and others. 2008. Recruitment of PCM1 to the centrosome by the cooperative action of DISC1 and BBS4: a candidate for psychiatric illnesses. Arch Gen Psychiatry 65:996–1006.
Khairova RA, Machado-Vieira R, Du J, Manji HK. 2009. A potential role for pro-inflammatory cytokines in regulating synaptic plasticity in major depressive disorder. Int J Neuropsychopharmacol 12:561–78.
Knopfel T, Lin MZ, Levskaya A, Tian L, Lin JY, Boyden ES. 2010. Toward the second generation of optogenetic tools. J Neurosci 30:14998–5004.
Kubo K, Honda T, Tomita K, Sekine K, Ishii K, Uto A, and others. 2010a. Ectopic Reelin induces neuronal aggregation with a normal birthdate-dependent “inside-out” alignment in the developing neocortex. J Neurosci 30:10953–66.
Kubo K, Tomita K, Uto A, Kuroda K, Seshadri S, Cohen J, and others. 2010b. Migration defects by DISC1 knockdown in C57BL/6, 129X1/SvJ, and ICR strains via in utero gene transfer and virus-mediated RNAi. Biochem Biophys Res Commun 400:631–7.
Langevin LM, Mattar P, Scardigli R, Roussigne M, Logan C, Blader P, and others. 2007. Validating in utero electroporation for the rapid analysis of gene regulatory elements in the murine telencephalon. Dev Dyn 236:1273–86.
Lewis DA, Sweet RA. 2009. Schizophrenia from a neural circuitry perspective: advancing toward rational pharmacological therapies. J Clin Invest 119:706–16.
LoTurco J, Manent JB, Sidiqi F. 2009. New and improved tools for in utero electroporation studies of developing cerebral cortex. Cereb Cortex 19 Suppl:i120–5.
Madisen L, Zwingman TA, Sunkin SM, Oh SW, Zariwala HA, Gu H, and others. 2010. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci 13:133–40.
Manent JB, Wang Y, Chang Y, Paramasivam M, LoTurco JJ. 2009. Dcx re-expression reduces subcortical band heterotopia and seizure threshold in an animal model of neuronal migration disorder. Nat Med 15:84–90.
Matsuda T, Cepko CL. 2007. Controlled expression of transgenes introduced by in vivo electroporation. Proc Natl Acad Sci USA 104:1027–32.
McCarley RW, Wible CG, Frumin M, Hirayasu Y, Levitt JJ, Fischer IA, and others. 1999. MRI anatomy of schizophrenia. Biol Psychiatry 45:1099–119.
McClellan JM, Susser E, King MC. 2007. Schizophrenia: a common disease caused by multiple rare alleles. Br J Psychiatry 190:194–9.
Miyagi S, Saito T, Mizutani K, Masuyama N, Gotoh Y, Iwama A, and others. 2004. The Sox-2 regulatory regions display their activities in two distinct types of multipotent stem cells. Mol Cell Biol 24:4207–20.
Nakahira E, Yuasa S. 2005. Neuronal generation, migration, and differentiation in the mouse hippocampal primoridium as revealed by enhanced green fluorescent protein gene transfer by means of in utero electroporation. J Comp Neurol 483:329–40.
Nakanishi H, Higuchi Y, Kawakami S, Yamashita F, Hashida M. 2010. piggyBac transposon-mediated long-term gene expression in mice. Mol Ther 18:707–14.
Nestler EJ, Hyman SE. 2010. Animal models of neuropsychiatric disorders. Nat Neurosci 13:1161–9.
Niwa M, Kamiya A, Murai R, Kubo K, Gruber AJ, Tomita K, and others. 2010. Knockdown of DISC1 by in utero gene transfer disturbs postnatal dopaminergic maturation in the frontal cortex and leads to adult behavioral deficits. Neuron 65:480–9.
O’Donovan MC, Craddock NJ, Owen MJ. 2009. Genetics of psychosis; insights from views across the genome. Hum Genet 126:3–12.
Owen MJ, Craddock N, O’Donovan MC. 2005. Schizophrenia: genes at last? Trends Genet 21:518–25.
Owen MJ, Craddock N, O’Donovan MC. 2010. Suggestion of roles for both common and rare risk variants in genome-wide studies of schizophrenia. Arch Gen Psychiatry 67:667–73.
Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E. 2008. Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry 63:801–8.
Punzo C, Cepko CL. 2008. Ultrasound-guided in utero injections allow studies of the development and function of the eye. Dev Dyn 237:1034–42.
Rapoport JL, Addington AM, Frangou S, Psych MR. 2005. The neurodevelopmental model of schizophrenia: update 2005. Mol Psychiatry 10:434–49.
Remedios R, Huilgol D, Saha B, Hari P, Bhatnagar L, Kowalczyk T, and others. 2007. A stream of cells migrating from the caudal telencephalon reveals a link between the amygdala and neocortex. Nat Neurosci 10:1141–50.
Rice H, Suth S, Cavanaugh W, Bai J, Young-Pearse TL. 2010. In utero electroporation followed by primary neuronal culture for studying gene function in subset of cortical neurons. J Vis Exp 44. pii: 2103.
Saito T. 2006. In vivo electroporation in the embryonic mouse central nervous system. Nat Protoc 1:1552–8.
Saito T, Nakatsuji N. 2001. Efficient gene transfer into the embryonic mouse brain using in vivo electroporation. Dev Biol 240:237–46.
Sauvageot CM, Stiles CD. 2002. Molecular mechanisms controlling cortical gliogenesis. Curr Opin Neurobiol 12:244–9.
Sebat J, Levy DL, McCarthy SE. 2009. Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders. Trends Genet 25:528–35.
Tabata H, Nakajima K. 2001. Efficient in utero gene transfer system to the developing mouse brain using electroporation: visualization of neuronal migration in the developing cortex. Neuroscience 103:865–72.
Tan HY, Callicott JH, Weinberger DR. 2009. Prefrontal cognitive systems in schizophrenia: towards human genetic brain mechanisms. Cogn Neuropsychiatry 14:277–98.
van Berckel BN, Bossong MG, Boellaard R, Kloet R, Schuitemaker A, Caspers E, | others. 2008. Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography study. Biol Psychiatry 64:820–2.
Wang X, Qiu R, Tsark W, Lu Q. 2007. Rapid promoter analysis in developing mouse brain and genetic labeling of young neurons by doublecortin-DsRed-express. J Neurosci Res 85: 3567–73.
Yoshida A, Yamaguchi Y, Nonomura K, Kawakami K, Takahashi Y, Miura M. 2010. Simultaneous expression of different transgenes in neurons and glia by combining in utero electroporation with the To12 transposon-mediated gene transfer system. Genes Cells 15:501–12.
Young-Pearse TL, Bai J, Chang R, Zheng JB, LoTurco JJ, Selkoe DJ. 2007. A critical function for beta-amyloid precursor protein in neuronal migration revealed by in utero RNA interference. J Neurosci 27:14459–69.
Young-Pearse TL, Suth S, Luth ES, Sawa A, Selkoe DJ. 2010. Biocemical and functional interaction of disrupted-in-schizophrenia 1 and amyloid precursor protein regulates neuronal migration during mammalian cortical development. J Neurosci 30:10431–40.
Zhang F, Gradinaru V, Adamantidis AR, Durand R, Airan RD, de Lecea L, and others. 2010. Optogenetic interrogation of neural circuits: technology for probing mammalian brain structures. Nat Protoc 5:439–56.
Cite article
Cite article
Cite article
OR
Download to reference manager
If you have citation software installed, you can download article citation data to the citation manager of your choice
Information, rights and permissions
Information
Published In
Article first published online: May 5, 2011
Issue published: April 2012
Keywords
History
Published online: May 5, 2011
Issue published: April 2012
PubMed: 21551077
Authors
Metrics and citations
Metrics
Article usage*
Total views and downloads: 614
*Article usage tracking started in December 2016
Articles citing this one
Web of Science: 44 view articles Opens in new tab
Crossref: 47
- Genetically encoded fluorescent sensors for imaging neuronal dynamics ...
- The cytoplasmic localization of ADNP through 14-3-3 promotes sex-depen...
- Methods to Assess the Role of Neurogenesis in Reproductive Behaviors o...
- A New Technical Approach for Cross-species Examination of Neuronal Wir...
- A companion to the preclinical common data elements for phenotyping se...
- Npas3 regulates stemness maintenance of radial glial cells and neurona...
- In Utero Electroporation for Manipulation of Specific Neuronal Populat...
- Rpsa Signaling Regulates Cortical Neuronal Morphogenesis via Its Ligan...
- RapID Cell Counter: Semi-Automated and Mid-Throughput Estimation of Ce...
- Adenosine A2A Receptors Contribute to the Radial Migration of Cortical...
- Epstein–Barr virus-based plasmid enables inheritable transgene express...
- Secreted retrovirus-like GAG-domain-containing protein PEG10 is regula...
- Combining electrophysiology and optogenetics for functional screening ...
- TAOK1 is associated with neurodevelopmental disorder and essential for...
- Glutathione S-transferase Pi (Gstp) proteins regulate neuritogenesis i...
- Subtle Roles of Down Syndrome Cell Adhesion Molecules in Embryonic For...
- Functional interrogation of neural circuits with virally transmitted o...
- Netrin‐G2 dysfunction causes a Rett‐like phenotype with areflexia
- In vivo epigenetic editing of Sema6a promoter reverses transcallosal d...
- The intellectual disability-associated CAMK2G p.Arg292Pro mutation act...
- RTF: a rapid and versatile tissue optical clearing method
- In vivo methods for acute modulation of gene expression in the central...
- Optogenetic stimulation: Understanding memory and treating deficits
- Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cor...
- Dendrite growth and the effect of ectopic Rheb expression on cortical ...
- Multiple events of gene manipulation via in pouch electroporation in a...
- Variation in a range of mTOR-related genes associates with intracrania...
- De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Inte...
- Methodological Approach for Optogenetic Manipulation of Neonatal Neuro...
- Variations in brain defects result from cellular mosaicism in the acti...
- A novel method of gene transduction to the murine endometrium using in...
- Early postnatal GABAA receptor modulation reverses deficits in neurona...
- Developmental Alcohol Exposure Impairs Activity-Dependent ...
- Altered Disrupted-in-Schizophrenia-1 Function Affects the Development ...
- Nonviral Gene Therapy of the Nervous System: Electroporation
- Animal models of gene–environment interaction in schizophrenia: A dime...
- A transportable, inexpensive electroporator for in utero...
- Social dysfunction and mental retardation
- Schizophrenia
- Application of in Utero Electroporation of G-Protein Coupled Receptor ...
- Transcriptional activity assessment of three different promoters for m...
- DISC1...
- Insights into Rapid Modulation of Neuroplasticity by Brain Estrogens
- Mouse models of gene–environment interactions in schizophrenia
- Electroporation: Past, present and future
- Genesis of Heterotopia in BCNU Model of Cortical Dysplasia, Detected b...
- High-performance and site-directed in utero electroporation by a tripl...
Figures and tables
Figures & Media
Tables
View Options
Get access
Access options
If you have access to journal content via a personal subscription, university, library, employer or society, select from the options below:
loading institutional access options
IHS members can access this journal content using society membership credentials.
IHS members can access this journal content using society membership credentials.
Alternatively, view purchase options below:
Purchase 24 hour online access to view and download content.
Access journal content via a DeepDyve subscription or find out more about this option.
