Genetically modified mice and cognition

Current Opinion in Neurobiology

Volumn 8, Issue 2, 1998, Pages 272-280

  Lipp, Hans Peter ^a   Wolfer, David P ^a  

^a UNIVERSITY OF ZURICH   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

ANIMAL BEHAVIOR; BRAIN REGION; COGNITION; HIPPOCAMPUS; LEARNING; MAZE TEST; MEMORY; MOUSE; NONHUMAN; PRIORITY JOURNAL; REVIEW; SWIMMING; TRANSGENIC ANIMAL;

EID: 0032052679     PISSN: 09594388     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0959-4388(98)80151-7     Document Type: Article

References (56)

1. Shors TJ, Matzel LD. Long-term potentiation: what's learning got to do with it? Behav Brain Sci. 20:1997;597-655.
2. Whishaw IQ, Tomie JA. Of mice and mazes - similarities between mice and rats on dry land but not water mazes. Physiol Behav. 60:1996;1191-1197.
3. Logue SF, Paylor R, Wehner JM. Hippocampal lesions cause learning deficits in inbred mice in the Morris water maze and conditioned-fear task. Behav Neurosci. 111:1997;104-113.
4. McNamara RK, Namgung U, Routtenberg A. Distinctions between hippocampus of mouse and rat: protein F1/GAP-43 gene expression, promoter activity, and spatial memory. Mol Brain Res. 40:1996;177-187.
5. Maguire EA, Frackowiak RSJ, Frith CD. Recalling routes around London: activation of the right hippocampus in taxi drivers. J Neurosci. 17:1997;7103-7110 No actual relation to mice, but a nice example of connectionist ideas of cognition with some implications for mouse work. Regional cerebral blood was recorded by means of positron emission tomography in taxi drivers watching films of driving through London, and, as control, sequences of famous landmarks around the world. Subjects also had to recall routes and famous landmarks. Images of regional activity patterns from different tasks were subtracted, revealing regions activated exclusively by one task. A network of cerebral structures of associative cortex was stimulated by recall, but the right hippocampus appeared to be activated by route recall exclusively. The authors suggest that the hippocampus might have a role in higher-level spatial manipulation and decision making. Lessons for rodent work: watch for side differences (see also [6]), check decision making and pay attention to reversal tasks. of special interest.
6. Chen Y, Constantini S, Trembovler V, Weinstock M, Shohami E. An experimental model of closed head injury in mice: pathophysiology, histopathology, and cognitive deficits. J Neurotrauma. 13:1996;557-568 Mice were knocked out by dropping weights on their heads. Memory retention after injury was tested in the Morris maze and found to be impaired up to 11 days. Histopathological analysis of the hippocampi showed that neuronal cell death was much more pronounced on the left than the right side. The origin of this asymmetry is unknown, but is a warning against neglecting functional left - right differences in the mouse brain. of special interest.
7. Bernasconi-Guastalla S, Wolfer DP, Lipp H-P. Hippocampal mossy fibers and swimming navigation in mice: correlations with size and left-right asymmetries. Hippocampus. 4:1994;53-64.
8. Cain DP, Saucier D, Hall J, Hargreaves EL, Boon F. Detailed behavioral analysis of water maze acquisition under APV or CNQX: contribution of sensorimotor disturbance to drug-induced acquisition deficits. Behav Neurosci. 110:1996;86-102.
9. Wolfer DP, Stagliar-Bozicevic M, Lipp H-P. Spatial memory and learning in transgenic mice: fact or artefact? News Physiol Sci. 13:1998;118-123 Presents a factor analysis of swimming navigation learning together with examples of how thigmotaxis can mask significant correlations of LTP with spatial learning. of special interest.
10. Owen EH, Logue SF, Rasmussen DL, Wehner JM. Assessment of learning by the Morris water task and fear conditioning in inbred mouse strains and F1 hybrids: implications of genetic background for single gene mutations and quantitative trait loci. Neuroscience. 80:1997;1087-1099.
11. Crawley JN, Belknap JK, Collins A, Crabbe JC, Frankel W, Henderson N, Hitzemann RJ, Maxson SC, Miner LL, Silva AJ, et al. Behavioral phenotypes of inbred mouse strains - implications and recommendations for molecular studies. Psychopharmacology. 132:1997;107-124.
12. Gerlai R. Gene-trageting studies of mammalian behavior: is it the mutation or the background genotype? Trends Neurosci. 19:1996;177-181 This target article has drawn widespread attention to the genetic background problem in analyzing transgenic mice, which is frequently attributable to the peculiarities of the 192 strain. The author's main argument is that a targeted locus remains flanked by 129 alleles, whereas in wild-type controls, the corresponding region contains only C57BL/6 alleles. Thus, a particular phenotype might not be attributable to homozygosity of the targeted locus, but to homozygosity of the flanking 129 alleles. One may note that this argument does not apply to phenotypes showing hybrid vigor, in which heterozygosity of many alleles improves performance beyond the level of the parental strains (see [10,13]). Within the same issue of the journal, there are useful commentaries by Crawley, Lathe and Crusio. of special interest.
13. Wolfer DP, Stagliar-Bozizevic M, Müller U, Lipp H-P. Assessing the effects of the 129Sv genetic background on swimming navigation learning in transgenic mutants: a study using mice with a modified beta-amyloid precursor gene. Brain Res. 771:1997;1-13 This study used mice known to show strong differences in the Morris maze and compared the parental strains C57BL/6 and 129Sv(ev) with hybrid samples (mixed C57/129 background) and mice carrying the mutation in a 129 strain. Hybrid mice performed as good or better than the parental strain C57BL/6. In line with this, the mutation effect on swimming navigation learning was most clearly observed in the mixed background, but was barely observable when comparing 129Sv(ev) mutant and wild-type mice, chiefly because the wild-type 129 mice performed nearly as poorly as the mutants. of special interest.
14. Montkowski A, Poettig M, Mederer A, Holsboer F. Behavioural performance in three substrains of mouse strain 129. Brain Res. 762:1997;12-18.
15. Simpson EM, Linder CC, Sargent EE, Davisson MT, Mobraaten LE, Sharp JJ. Genetic variation among 129 substrains and its importance for targeted mutagenesis in mice. Nat Genet. 16:1997;19-27 Embryonic stem cells for gene targeting are mostly obtained from various sublines of the 129 strain, such as 129/Sv(ev), pigmented, 129/Ola (pink eye diluted), 129/Ter, and 129/J. The authors present a detailed review of the history and genealogy of the substrains and report contaminations of some strains. A must for everyone working with knockout mice of 129 origin. of outstanding interest.
16. Bowes C, Li T, Frankel WN, Danciger M, Coffin JM, Applebury ML, Farber DB. Localization of a retroviral element within the rd gene coding for the beta subunit of cGMP phosphodiesterase. Proc Natl Acad Sci USA. 90:1993;2955-2959.
17. Lindner MD, Plone MA, Schaller T, Emerich DF. Blind rats are not profoundly impaired in the reference memory Morris water maze and cannot be clearly discriminated from rats with cognitive deficits in the cued platform task. Cogn Brain Res. 5:1997;329-333.
18. Nalbantoglu J, Tiradosantiago G, Lahsaini A, Poirier J, Goncalves O, Verge A, Momoli F, Welner SA, Massicotte G, Julien JP, Shapiro ML. Impaired learning and LTP in mice expressing the carboxy terminus of the Alzheimer amyloid precursor protein. Nature. 387:1997;500-505.
19. D'Hooge R, Nagels G, Westland CE, Mucke L, De Deyn PP. Spatial learning deficit in mice expressing human 751-amino acid beta-amyloid precursor protein. Neuroreport. 7:1996;2807-2811.
20. Haroutunian V, Zhou YL, Elder G, Li C, Lazzarini RA. Age-dependent spatial memory deficits in transgenic mice expressing the human mid-sized neurofilament gene. Mol Brain Res. 42:1996;62-70.
21. Hsiao KK, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang FS, Cole G. Correlative memory deficits, alpha-beta elevation, and amyloid plaques in transgenic mice. Science. 274:1996;99-102.
22. Demas GE, Nelson RJ, Krueger BK, Yarowsky PJ. Spatial memory deficits in segmental trisomic Ts65Dn mice. Behav Brain Res. 82:1996;85-92.
23. Smith DJ, Stevens ME, Sudanagunta SP, Bronson RT, Makhinson M, Watabe AM, Odell TJ, Fung J, Weier HUG, Cheng JF, Rubin EM. Functional screening of 2 mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Downs-syndrome. Nat Genet. 16:1997;28-36 The authors used an intriguing transgenic approach to decipher the enigma of impaired learning and cognitive capacities in Down's syndrome. They generated four transgenic mouse lines expressing differential segments of the trisomic human chromosome (in the form of artificial yeast chromosomes) and tested them in the Morris water maze and for open-field activity. They found mild impairment in acquisition of the task in only one line, probe trial deficits in two. Intriguingly, poor performance can apparently been narrowed down to region of the human chromosome that contains the homologue of the Drosophila gene minibrain. LTP was normal, but neuronal density increased. The approach of establishing an in vivo library of human chromosome segments transgenes in mice and testing them behaviorally is impressive but also daunting - who can afford to keep such a murine library? of outstanding interest.
24. D'Hooge R, Nagels G, Franck F, Bakker CE, Reyniers E, Storm K, Kooy RF, Oostra BA, Willems PJ, De Deyn PP. Mildly impaired water maze performance in male FMR1 knockout mice. Neuroscience. 76:1997;367-376.
25. Silva AJ, Frankland PW, Marowitz Z, Friedman E, Lazlo G, Cioffi D, Jacks T, Bourtchuladze R. A mouse model for the learning and memory deficits associated with neurofibromatosis type I. Nat Genet. 15:1997;281-284.
26. Tremml P, Lipp H-P, Müller U, Ricceri L, Wolfer DP. Neurobehavioral development, adult openfield exploration and swimming navigation learning in mice with a modified beta-amyloid precursor protein gene. Behav Brain Res. 1998;. in press.
27. Oitzl MS, Mulder M, Lucassen PJ, Havekes LM, Grootendorst J, Dekloet ER. Severe learning deficits in apolipoprotein e knockout mice in a water maze task. Brain Res. 752:1997;189-196.
28. Chen C, Tonegawa S. Molecular genetic analysis of synaptic plasticity, activity-dependent neural development, learning, and memory in the mammalian brain. Annu Rev Neurosci. 20:1997;157-184 A useful listing of mouse knockout studies and discussion of the relations between the various forms of LTP impairments, spatial learning and contextual conditioning. Other topics covered are developmental plasticity in somatosensory and cerebellar pathways. of special interest.
29. Miyakawa T, Yagi T, Kagiyama A, Niki H. Radial maze performance, open-field and elevated plus-maze behaviors in fyn-kinase deficient mice: further evidence for increased fearfulness. Mol Brain Res. 37:1996;145-150.
30. Huerta PT, Scearce KA, Farris SM, Empson RM, Prusky GT. Preservation of spatial learning in fyn tyrosine kinase knockout mice. Neuroreport. 7:1996;1685-1689.
31. Kogan JH, Frankland PW, Blendy JA, Coblentz J, Marowitz Z, Schütz G, Silva AJ. Spaced training induces normal long-term memory in CREB mutant mice. Curr Biol. 7:1997;1-11.
32. Silva AJ, Rosahi TW, Chapman PF, Marowitz Z, Friedman E, Frankland PW, Cestari V, Cioffi D, Südhof TC, Bourtchuladze R. Impaired learning in mice with abnormal short-lived plasticity. Curr Biol. 6:1996;1509-1518.
33. Huang Y-Y, Back ME, Lipp H-P, Zhuo M, Wolfer DP, Hawkins RD, Schoonjans L, Kandel ER, Godfraind J-M, Mulligan RC, et al. Mice lacking the gene encoding tissue-type plasminogen activator show a selective interference with late phase LTP in both Schaffer collateral and mossy fiber pathways. Proc Natl Acad Sci USA. 93:1996;8699-8704.
34. Brambilla R, Gnesutta N, Minichiello N, White G, Roylance A, Herron C, Ramsey M, Wolfer DP, Cestari V, Rossi-Arnaud C, Grant SGN, et al. A role for the Ras signaling pathway in synaptic transmission and long-term memory. Nature. 390:1997;281-286 Mice deficient for Ras, an intracellular signalling pathway protein in many brain areas and body organs, were studied in the Morris maze, radial maze, contextual fear conditioning, open-field, one-way passive avoidance, and two-way avoidance learning. They showed no deficits in swimming navigation and radial maze learning, but were massively impaired in active two-way avoidance learning, and 24 h retention in both contextual fear conditioning and passive one-way avoidance, suggesting impaired memory consolidation only for fear-related learning. In spite of the wide distribution of Ras in the brain, LTP deficits were found in the amygdala but not in the hippocampus. The reasons for such regionally specific changes in electrophysiology are unknown. of special interest.
35. Lu YM, Jia ZP, Janus C, Henderson JT, Gerlai R, Wojtowicz JM, Roder JC. Mice lacking metabotropic glutamate receptor 5 show impaired learning and reduced CA1 long-term potentiation (LTP) but normal CA3 LTP. J Neurosci. 17:1997;5196-5205.
36. Gerlai R, Henderson JT, Roder JC, Jia M. Multiple behavioral anomalies in GluR2 mutant mice. Behav Brain Res. 1998;. in press.
37. Rousse I, Beaulieu S, Rowe W, Meaney MJ, Barden N, Rochford J. Spatial memory in transgenic mice with impaired glucocorticoid receptor function. Neuroreport. 8:1997;841-845 A nice example of how thigmotaxis and impaired response flexibility in the water maze might result in poor probe trial scores. Transgenic mice bearing a DNA antisense construct reducing the expression of the glucocorticoid receptor by more than 50% in hypothalamus, hippocampus and cortex, were tested in the Morris water maze and for radial maze learning. Transgenics were extraordinarily impaired in both tasks in the Morris maze, both in the invisible and visible platform version. Examples of swim paths given indicate severe thigmotaxis; radial maze errors (unconfined test situation) reveal altered behavioral strategies. of special interest.
38. Forrest D, Hanebuth E, Smeyne RJ, Everds N, Stewart CL, Wehner JM, Currant T. Recessive resistance to thyroid hormone in mice lacking thyroid hormone receptor β: evidence for tissue-specific modulation of receptor function. EMBO J. 15:1996;3006-3015.
39. Montkowski A, Holsboer F. Intact spatial learning and memory in transgenic mice with reduced BDNF. Neuroreport. 8:1997;779-782.
40. Nosten-Bertrand M, Errington ML, Murphy KP, Tokugawa Y, Barboni E, Kozlova E, Michalovich D, Morris RGM, Silver J, Stewart CL, et al. Normal spatial learning despite regional inhibition of LTP in mice lacking Thy-1. Nature. 379:1996;826-829.
41. Errington ML, Bliss TVP, Morris RJ, Laroche S, Davis S. Long-term potentiation in awake mutant mice. Nature. 387:1997;666-667 The authors studied a sample of the same Thy-1-deficient mice as described in [40]; however, in this study, the mice could move freely. They found that dentate LTP was suppressed in only about half of the mice. Specifically, this implies that individual variations in GABA-mediated inhibition may strongly affect LTP. More generally, it indicates that correlations between neurophysiology and spatial learning should be assessed by studying the variables in the same animal and not by subjecting different groups to different investigations. Finally, it shows that results obtained in slices or in anesthetized mice cannot be extrapolated to real life. of special interest.
42. Wolfer DP, Mohajeri HM, Lipp H-P, Schachner M. Increased behavioral flexibility and reduced retention in the Morris watermaze in transgenic mice ectopically expressing the neural cell adhesion molecule L1 in astrocytes. Eur J Neurosci. 10:1998;708-717 A study that shows an unusual finding of improved spatial learning behavior in genetically modified mice. A large sample of transgenic ice of different genetic background (n=90) was trained in the Morris maze under a schedule that also included reversal learning. Transgenic mice performed better in the early phases of acquisition and during reversal. A detailed analysis of errors combined with factor analysis revealed that the superiority was attributable to a slight yet significant improvement in searching behavior, most evident in phases in which the mice had to adapt to new situations. The authors concluded that ectopically expressed L1 may improve behavioral flexibility, but concomitantly reduces spatial memory scores because L1-transgenic mice were quicker at looking for the new location of the platform. of special interest.
43. Griebel G, Blanchard DC, Blanchard RJ. Evidence that the behaviors in the Mouse Defense Test Battery relate to different emotional states: a factor analytic study. Physiol Behav. 60:1996;1255-1260.
44. Crawley JN, Paylor R. A proposed test battery and constellations of specific behavioral paradigms to investigate the behavioral phenotypes of transgenic and knockout mice. Horm Behav. 31:1997;197-211 A much needed, albeit not complete, compendium of mouse behavior tests enabling molecular biologists to go beyond the Morris-maze/contextual fear scheme in the analysis of mouse behavior. of special interest.
45. Thinus-Blanc C, Save E, Rossi-Arnaud C, Tozzi A, Ammassari-Teule M. The differences shown by C57BL/6 and DBA/2 inbred mice in detecting spatial novelty are subserved by a different hippocampal and parietal cortex interplay. Behav Brain Res. 80:1996;33-40 Deals not with genetically modified mice, but uses a test that could complement easily the characterization of behavioral phenotypes related to cognition. The principle is that mice are repeatedly exposed to an open-field situation that contains various objects. Objects can then either be displaced (spatial novelty) or replaced by a new object in the same location. The actual data show genetic differences in lesion effects. of special interest.
46. Silva AJ, Simpson EM, Takahashi SJ, Lipp H-P, Nakanishi S, Wehner JM, Giese KP, Tully T, Abel T, Chapman PF, et al. Mutant mice and neuroscience: recommendations concerning genetic background. Neuron. 19:1997;755-759 Summarizes a Cold Spring Harbor Meeting discussing the genetic background problem in behavioral analysis of genetically modified mice. Consensus was reached that behavioral studies should be done in hybrids derived from two inbred strains, ideally in F1 hybrids from two strains carrying the backcrossed mutation. Gives also useful recommendations of how to keep and maintain targeted disruptions. of special interest.
47. Kojima N, Wang J, Mansuy IM, Grant SG, Mayford M, Kandel ER. Rescuing impairment of long-term potentiation in fyn-deficient mice by introducing fyn transgene. Proc Natl Acad Sci USA. 94:1997;4761-4765.
48. Molinari S, Battini R, Ferrari S, Pozzi L, Killcross AS, Robbins TW, Jouvenceau A, Billard JM, Dutar P, Lamour Y, et al. Deficits in memory and hippocampal long-term potentiation in mice with reduced calbindin D28k expression. Proc Natl Acad Sci USA. 93:1996;8028-8033.
49. Abel T, Nguyen PV, Barad M, Deuel TAS, Kandel ER. Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell. 88:1997;615-626.
50. Tsien JZ, Huerta PT, Tonegawa S. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell. 87:1996;1327-1338.
51. Mayford M, Bach ME, Huang YY, Wang L, Hawkins RD, Kandel ER. Control of memory formation through regulated expression of a CaMKII transgene. Science. 274:1996;1678-1683.
52. Cavallaro S, Meiri N, Yi CL, Musco S, Ma W, Goldberg J, Alkon DL. Late memory-related genes in the hippocampus revealed by RNA fingerprinting. Proc Natl Acad Sci USA. 94:1997;9669-9673.
53. Davis S, Bliss TVP, Dutrieux G, Laroche S, Errington ML. Induction and duration of long-term potentiation in the hippocampus of the freely moving mouse. J Neurosci Methods. 75:1997;75-80.
54. Rotenberg A, Mayford M, Hawkins RD, Kandel ER, Muller RU. Mice expressing activated CaMKII lack low frequency LTP and do not form stable place cells in the CA1 region of the hippocampus. Cell. 87:1996;1351-1361.
55. McHugh TJ, Blum KI, Tsien JZ, Tonegawa S, Wilson MA. Impaired hippocampal representation of space in CA1-specific NMDAR1 knockout mice. Cell. 87:1996;1339-1349 This paper, published in the same issue of Cell as [50,54], analyzes the spatial cell properties of the knockout mice lacking NMDA receptors in the hippocampal subregion CA1 as described in [50], using a multielectrode array recording from mice moving in a straight and in an L-shaped track. Perhaps surprisingly, at least in view of their distinct spatial learning deficits, the firing of single cells was not affected. However, the spatial neurons in the knockout mice showed uncorrelated activity and less spatial selectivity - features that may be responsible for the impaired learning in the Morris maze - as a covariate of spatial memory or thigmotaxis. of outstanding interest.
56. αΔ mice. Science. 279:1998;867-869.