LTP, NMDA, genes and learning

Current Opinion in Neurobiology

Volumn 7, Issue 2, 1997, Pages 235-242

  Cain, Donald Peter ^a  

^a UNIVERSITY OF WESTERN ONTARIO   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

N METHYL DEXTRO ASPARTIC ACID; N METHYL DEXTRO ASPARTIC ACID RECEPTOR;

CELL FUNCTION; GENE; HIPPOCAMPUS; HYPOTHESIS; LEARNING; LONG TERM POTENTIATION; NEUROTRANSMISSION; NONHUMAN; PRIORITY JOURNAL; REVIEW; STATE DEPENDENT LEARNING; SYNAPTIC TRANSMISSION;

EID: 0031006320     PISSN: 09594388     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0959-4388(97)80012-8     Document Type: Article

References (75)

1. Hebb DO. Organization of Behavior. 1949;Wiley, New York.
2. Morris RGM, Davis M. The role of NMDA receptors in learning and memory. Collingridge GL, Watkins JC. edn 2 The NMDA Receptor. 1994;340-375 Oxford University Press, Oxford.
3. of special interest Barnes CA. Involvement of LTP in memory: are we 'searching under the street light'? Neuron. 15:1995;751-754 A thoughtful review that discusses promising research in the context of what it would take to prove or disprove a major role for LTP in learning.
4. of special interest Maren S, Fanselow MS. The amygdala and fear conditioning: has the nut been cracked? Neuron. 16:1996;237-240 A thoughtful review of the evidence on the neural basis of experience-dependent modification of sensory processing, including a discussion of its strengths and limitations in the context of the NMDA - LTP hypothesis.
5. of special interest Riedel G, Reymann KG. Metabotropic glutamate receptors in hippocampal long-term potentiation and learning and memory. Acta Physiol Scand. 157:1996;1-19 This review is similar to [3,4] but is longer and focused on recent work with metabotropic glutamate receptor agonists and antagonists in learning and memory.
6. of outstanding interest McEachem JC, Shaw CA. An alternative to the LTP orthodoxy: a plasticity-pathology continuum model. Brain Res Rev. 22:1996;51-92 The first review to openly critique 'the LTP orthodoxy' in a comprehensive way. The authors offer many incisive criticisms of current LTP - learning research that are certain to challenge current views, but which need to be confronted if progress is to be made. Insight into this process is given in the form of comments and criticisms from reviewers of the draft manuscript that the authors incorporated into the final published version. The result makes for fascinating reading. As an alternative function for LTP, the authors offer a model that incorporates LTP, along with LTD and kindling, into a neuroplasticity/pathology continuum. Whatever one's views and whatever the outcome of LTP research, this and the next review[7] must be regarded as signs of the health and vigor of the field.
7. of outstanding interest Shors TJ, Matzel LD. Long-term potentiation: what's learning got to do with it? Behav Brain Sci. 1997; This review is similar in scope and import to [6]. The authors suggest a different alternative to the LTP orthodoxy - that LTP serves as an attentional mechanism in brain function. Whatever one's views, this review is to be welcomed in its attempt to provoke a critical look at LTP research and to suggest an heuristic alternative.
8. Morris RGM. Synaptic plasticity and learning: selective impairment of learning in rats and blockade of long-term potentiation in vivo by the N-methyl-D-aspartate receptor antagonist AP5. J Neurosci. 9:1989;3040-3057.
9. Morris RGM, Anderson E, Lynch GS, Baudry M. Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature. 319:1986;774-776.
10. Bliss TVP, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 31:1993;31-39.
11. Monyer H, Burnashev N, Laurie D, Sakmann B, Seeberg P. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron. 12:1994;529-540.
12. Alford S, Brodin L. The role of NMDA receptors in synaptic integration and the organization of motor patterns. Collingridge GL, Watkins JC. edn 2 The NMDA Receptor. 1994;277-293 Oxford University Press, Oxford.
13. of outstanding interest Cain DP, Saucier D, Hall J, Hargreaves EL, Boon F. Detailed behavioral analysis of water maze acquisition under APV or CNQX: contribution of sensorimotor disturbances to drug-induced acquisition deficits. Behav Neurosci. 110:1996;86-102 With [48], this paper is the most detailed behavioral analysis of water maze acquisition available. The authors report sensorimotor disturbances in naive rats with an intraventricularly administered NMDA antagonist, but few sensorimotor disturbances and rapid learning in rats made familiar with the general task requirements by non-spatial pre-training.
14. Dai H, Carey RJ. The NMDA antagonist MK-801 can impair attention to exteroceptive stimuli. Behav Brain Res. 62:1994;149-156.
15. Hargreaves EL, Cain DP. Hyperactivity, hyper-reactivity, and sensorimotor deficits induced by low doses of the N-methyl-D-aspartate non-competitive channel blocker MK-801. Behav Brain Res. 47:1992;23-33.
16. Tan S, Kirk RC, Abraham WC, McNaughton N. Effects of the NMDA antagonists CPP and MK-801 on delayed conditional discrimination. Psychopharmacology. 98:1989;556-560.
17. Tang AH, Ho PM. Both competitive and non-competitive antagonists of N-methyl-D-aspartic acid disrupt brightness discrimination in rats. Eur J Pharmacol. 151:1988;143-146.
18. Headley PM, Grillner S. Excitatory amino acids and synaptic transmission: the evidence for a physiological function. Trends Pharmacol Sci. 11:1990;205-211.
19. Damsma G, Robertson GS, Tham C-S, Fibiger HC. Dompaminergic regulation of striatal acetylcholine release: importance of D1 and N-methyl-D-aspartate receptors. J Pharmacol Exp Ther. 259:1991;1064-1069.
20. of special interest Healey DJ, Meador-Woodruff JH. Differential regulation, by MK-801, of dopamine receptor gene expression in rat nigrostriatal and mesocorticolimbic systems. Brain Res. 708:1996;38-44 In situ hybridization was used to measure dopamine receptor mRNA levels in the cortex, nucleus accumbens, basal ganglia, and midbrain. The NMDA antagonist MK-801 differentially regulated dopamine receptor mRNAs in these regions, possibly affecting long-term motor and other functions. This example of interaction effects between one receptor antagonist and receptors for another neurotransmitter indicates the complex interactions that are possible with antagonist treatment, with the potential to affect behavior in learning research.
21. Salt TE. NMDA receptors and their interactions with other excitatory amino acid receptors in synaptic transmission in the mammalian central nervous system. Collingridge GL, Watkins JC. edn 2 The NMDA Receptor, 1994;252-264 Oxford University Press, Oxford.
22. Whitton PS, Maione S, Biggs CS, Fowler LJ. N-methyl-D-aspartate receptors modulate extracellular dopamine concentration and metabolism in rat hippocampus and striatum in vivo. Brain Res. 635:1994;312-316.
23. of outstanding interest Binns KE, Salt TE. Importance of NMDA receptors for multimodal integration in the deep layers of the cat superior colliculus. J Neurophysiol. 75:1996;920-932 Responses to visual, auditory, and somatosensory stimuli alone and in combination were recorded from superior colliculus neurons to assess multimodal sensory integration. Iontophoretically applied AP5 (an NMDAR antagonist) reduced responses to stimuli presented alone and in combination. The responses to stimulus combinations were reduced to a greater extent than the sum of the reductions to the same stimuli presented alone. NMDARs are of major importance in the integration of input from different modalities. This is a very important contribution to the literature on NMDAR physiology and is relevant to the complex sensorimotor effects of NMDA antagonists.
24. Daw NW, Stein PSG, Fox K. The role of NMDA receptors in information processing. Annu Rev Neurosci. 16:1993;207-222.
25. Evans RH. The importance of NMDA receptors in the processing of spinal primary afferent input. Collingridge GL, Watkins JC. edn 2 The NMDA Receptor. 1994;266-275 Oxford University Press, Oxford.
26. Fox K, Daw NW. A model for the action of NMDA conductances in the visual cortex. Neural Computation. 4:1992;59-83.
27. Fox K, Sato H, Daw N. The location and function of NMDA receptors in cat and kitten visual cortex. J Neurosci. 9:1990;2443-2454.
28. Sillito A, Murphy P, Salt T, Moody C. Dependence of retinogeniculate transmission in the cat on NMDA receptors. J Neurophysiol. 63:1990;347-355.
29. of outstanding interest Cain DP, Saucier D, Boon F. Testing hypotheses of spatial learning: the role of NMDA receptors and NMDA receptor-mediated long term potentiation. Behav Brain Res. 84:1997;179-193 An extension of the experiment described in [47] to evaluate the role of NMDA-dependent LTP in spatial learning. CGS-19755, an NMDAR antagonist, was given systemically and its effects evaluated on dentate LTP and spatial learning in the same rats that had been familiarized with the general task requirements by non-spatial pre-training. CGS-19755 blocked LTP, and the rats learned the location of the hidden platform in the water maze as quickly as controls. NMDA antagonism also impaired visual discrimination in a Y-maze and visible platform discrimination in the water maze pool.
30. Murray TK, Ridley RM, Snape MF, Cross AJ. The effect of dizocilpine (MK-80) on spatial and visual discrimination in the rat. Behav Pharmacol. 6:1995;540-549.
31. Oye I, Paulsen O, Maurset A. Effects of ketamine on sensory perception: evidence for a role of N-methyl-D-aspartate receptors. J Pharmacol Exp Ther. 260:1992;1209-1213.
32. Sveinbjornsdottir S, Sander JWAS, Upton D, Thompson PJ, Patsalos PN, Hirt D, Emre M, Lowe D, Duncan JS. The excitatory amino acid antagonist D-CPP-ene (SDZ EAA-494) in patients with epilepsy. Epilepsy Res. 16:1993;165-174.
33. Suga N, Olsen JF, Butman JA. Specialized subsystems for processing biologically important complex sounds: cross correlation analysis for ranging in the bat's brain. Cold Spring Harb Symp Quant Biol. 55:1990;585-597.
34. Davies J, Miller AJ, Sheardown MJ. Amino acid receptor mediated excitatory synaptic transmission in the cat red nucleus. J Physiol. 376:1986;13-29.
35. Thompson AM, West DC, Lodge D. An N-methyl-D-aspartate receptor-mediated synapse in rats cerebral cortex: a site of action of ketamine? Nature. 313:1986;479-481.
36. Herron CE, Lester RAJ, Coan EJ, Collingridge GL. Frequency-dependent involvement of NMDA receptors in the hippocampus: a novel synaptic mechanism. Nature. 322:1986;265-268.
37. Keller BU, Konnerth A, Yaari Y. Patch clamp analysis of excitatory synaptic currents in granule cells of rat hippocampus. J Physiol. 435:1991;275-293.
38. Lambert JDC, Jones RSG. A reevaluation of excitatory amino acid-mediated synaptic transmission in rat dentate gyrus. J Neurophysiol. 64:1990;119-132.
39. Abraham WC, Mason SE. Effects of the NMDA receptor/channel antagonists CPP and MK801 on hippocampal field potentials and long-term potentiation in anesthetized rats. Brain Res. 462:1988;40-46.
40. Walker DL, Gold PE. Intrahippocampal administration of both the D- and the L-isomers of AP5 disrupt spontaneous alternation behavior and evoked potentials. Behav Neural Biol. 62:1994;151-162.
41. Bashir ZI, Alford S, Davies SN, Randall AD, Collingridge GL. Long-term potentiation of NMDA receptor-mediated synaptic transmission in the hippocampus. Nature. 349:1991;156-158.
42. Gutnikof SA, Rawlins JNP. Systemic NMDA antagonist CGP-37849 produces non-specific impairment in a working memory task: the effect does not resemble those of AP5 and of lesions of the hippocampus of fornix. Neuropsychologia. 34:1996;311-314.
43. DeVietti TL, Pellis SM, Pellis VC, Teitelbaum P. Previous experience disrupts atropine-induced stereotyped 'trapping' in rats. Behav Neurosci. 99:1985;1128-1141.
44. of special interest Mabry TR, McCarthy R, Gold PE, Foster TC. Age and stress history effects on spatial performance in a swim task in Fischer-344 rats. Neurobiol Learn Mem. 66:1996;1-10 Signs of stress are often seen in naive rats when first placed into the water maze. This study asked whether stress contributes to the age-related impairments that are seen in old rats in this task. Immersion in water for 15 min over 28 days reduced the age-related impairment, suggesting that a portion of the impairment is secondary to age-related stress responses. The effect is similar to Morris' [8] non-spatial pre-training and is well worth additional research.
45. Steinberg H, Rushton R, Tinson C. Modification of the effects of an amphetamine-barbiturate mixture by the past experience of rats. Nature. 192:1961;533-535.
46. Whishaw IQ. Dissociating performance and learning deficits on spatial navigation tasks in rats subjected to cholinergic muscarinic blockade. Brain Res Bull. 23:1989;347-358.
47. of outstanding interest Saucier D, Cain DP. Spatial learning without NMDA receptor-dependent long-term potentiation. Nature. 378:1995;186-189 This study addressed the issue of whether NMDA-mediated dentate gyrus LTP is required for rats to learn the location of a hidden platform in the water maze. The same rats were used in the electrophysiological and behavioral portions of the experiment. Non-spatially pre-trained rats whose LTP was blocked learned the location of the hidden platform as quickly as controls.
48. of outstanding interest Saucier D, Hargreaves EL, Boon F, Vanderwolf CH, Cain DP. Detailed behavioral analysis of water maze acquisition under systemic NMDA or muscarinic antagonism: nonspatial pretraining eliminates spatial learning deficits. Behav Neurosci. 110:1996;103-116 An extension of the approach applied in [13], using systemically administered NMDA and muscarinic antagonists, with similar results.
49. of special interest Cain DP. Prior nonspatial pretraining eliminates sensorimotor disturbances and impairments in water maze learning caused by diazepam. Psychopharmacology. 1997; Diazepam produced water maze acquisition impairments and sensorimotor disturbances very similar to those produced by NMDA antagonists. It did this without affecting swim speed or impairing acquisition of a visible platform task, which indicates that these behavioral measures may not be sufficient to reveal sensorimotor disturbances relevant to performance of the task. More detailed behavioral measures appear to be required to fully evaluate the possible role of sensorimotor disturbances in acquisition impairments.
50. of outstanding interest Bannerman DM, Good MA, Butcher SP, Ramsay M, Morris RGM. Distinct components of spatial learning revealed by prior training and NMDA receptor blockade. Nature. 378:1995;182-186 Rats given spatial training in one pool can learn the location of a hidden platform in a different pool despite blockade of dentate LTP with AP5. A second group given only non-spatial pre-training in the first pool was impaired under AP5 in the second pool. Demonstrates the complexity of the water maze task and shows that robust spatial learning can occur without NMDAR-mediated LTP in the dentate gyrus.
51. Silva AJ, Paylor R, Wehner JM, Tonegawa S. Impaired spatial learning in alpha-calcium-calmodulin kinase II mutant mice. Science. 257:1992;206-211.
52. Grant SGN, O'Dell TJ, Karl KA, Stein PL, Soriano P, Kandel ER. Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice. Science. 258:1992;1903-1910.
53. Sakimura K, Kutsuwada T, Ito I, Manabe T, Takayama C, Kushiya E, Yagi T, Aizawa S, Inoue Y, Sugiyama H, Mishina M. Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor 1 subunit. Nature. 373:1995;151-155.
54. of special interest Gerlai R. Gene-targeting studies of mammalian behavior: is it the mutation or the background genotype? Trends Neurosci. 19:1996;177-181 An important discussion of the difficulties of interpreting phenotypic changes in knock-out mice, including changes in behavior. Two topics receive close attention: effects of deletion of one gene on expression of other genes and the effects of genes in the background strain.
55. of outstanding interest 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 Possibly an example of behavioral abnormalities discussed in [54], this study shows that fyn knock-out mice spend much of their time floating in the water maze without swimming, a phenotype that leads to elevated platform search times whether there is a specific learning impairment or not. The knock-out mice swam well when their hind feet were stimulated manually. When this was done briefly at the start of trials, the mice could learn the platform location as effectively as wild-type controls.
56. Umemori H, Sato S, Yagi T, Aizawa S, Yamamoto T. Initial events of myelination involve Fyn tyrosine kinase signaling. Nature. 367:1994;572-576.
57. Huang Y-Y, Kandel ER, Varshavsky L, Brandon EP, Qi M, Idzerda RL, McKnight GS, Bourtchouladze R. A genetic test of the effects of mutations in PKA on mossy fiber LTP and its relation to spatial and contextual learning. Cell. 83:1995;1211-1222.
58. of special interest Nosten-Bertrand M, Errington ML, Murphy KPSJ, 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 Mice lacking the gene for Thy-1 are reported to have normal hippocampal CA1 LTP but strongly inhibited dentate LTP. These mice were able to learn the location of a hidden platform as effectively as wild-type controls.
59. Motro B, Wojtowicz JM, Bernstein A, Van Der Kooy D. Steel mutant mice are deficient in hippocampal learning but not long-term potentiation. Proc Natl Acad Sci USA. 93:1996;1808-1813.
60. Mayford M, Wang J, Kandel ER, O'Dell TJ. CaMKII regulates the frequency-response function of hippocampal synapses for the production of both LTD and LTP. Cell. 81:1995;891-904.
61. Bach ME, Hawkins RD, Osman M, Kandel ER, Mayford M. Impairment of spatial but not contextual memory in CaMKII mutant mice with a selective loss of hippocampal LTP in the range of the theta frequency. Cell. 81:1995;905-915.
62. of outstanding interest 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 The authors describe a CaMKII transgenic mutant that displays reversible (in adulthood) hippocampal CA1 LTP and spatial learning impairments. A different strain of mutant with expression of the transgene in the amygdala and striatum displayed a reversible fear conditioning deficit.
63. of outstanding interest 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 The transgenic mice developed in [62] were found to have abnormal hippocampal CA1 place cells, which appears to account for their poor spatial learning. These two papers [62,63] are an important advance in linking place cell function to spatial learning.
64. of special interest 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. 87:1996;1317-1326 Development of a regionally and temporally limited NMDAR knock-out is described. The mice lack NMDARs only in the hippocampal CA1 region. This development is a major advance in studying the genetic control of brain mechanisms involved in behavior.
65. of outstanding interest Tsien JZ, Huerta J, Tonegawa S. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell. 87:1996;1327-1338 The mutants developed in [64] were found to lack CA1 EPSCs and LTP and were impaired in spatial learning. The results suggest that CA1 LTP is essential for spatial learning.
66. of outstanding interest McHugh TJ, Blum KI, Tsien J, Tonegawa S, Wilson M. Impaired hippocampal representation of space in CA1-specific NMDAR1 knockout mice. Cell. 87:1996;1339-1349 The mutants developed in [64] were found to have abnormal hippocampal CA1 place cells, which appears to account for their poor spatial learning. As with the two papers mentioned above [62,63], these three papers [64,65,66] are an important advance in linking place cell function to spatial learning.
67. Whishaw IQ, Vanderwolf CH. Hippocampal EEG and behavior: changes in amplitude and frequency of RSA (theta rhythm) associated with spontaneous and learned movement patterns in rats and cats. Behav Biol. 8:1973;461-484.
68. Vanderwolf CH. Cerebral activity and behavior: control by central cholinergic and serotonergic systems. Int Rev Neurobiol. 30:1988;225-340.
69. Fordyce DE, Farrar RP. Enhancement of spatial learning in F344 rats by physical activity and related learning-associated alterations in hippocampal and cortical cholinergic functioning. Behav Brain Res. 46:1991;123-133.
70. of outstanding interest Gutnikof SA, Gaffan D. Systemic NMDA receptor antagonist CGP-40116 does not impair memory acquisition but protects against NMDA neurotoxicity in rhesus monkeys. J Neurosci. 16:1996;4041-4045 This study is important for its use of NMDA antagonists in rhesus monkeys performing an 'object-in-place' visual memory task that is analogous to human object memory tasks. The small (<3%) increase in errors, which was present in both acquisition and retention, was attributed to non-specific effects.
71. of outstanding interest Feldman DE, Brainard MS, Knudsen EI. Newly learned auditory responses mediated by NMDA receptors in the owl inferior colliculus. Science. 217:1996;525-528 Unit recordings were made from the inferior colliculus of barn owls that had worn visual displacing prisms to induce experience-dependent changes in visual - auditory receptive fields. Newly learned tectal auditory responses were significantly reduced by the NMDA antagonists, suggesting that the learned responses were dependent on NMDA activity. This promising approach merits additional work to determine the synapse(s) at which the changes take place and whether natural LTP occurs there.
72. Miserendino MJD, Sananes CB, Melia KR, Davis M. Blocking of acquisition but not expression of conditioned fear-potentiated startle by NMDA antagonists in the amygdala. Nature. 345:1990;716-718.
73. of outstanding interest Rogan MT, LeDoux JE. LTP is accompanied by commensurate enhancement of auditory-evoked responses in a fear conditioning circuit. Neuron. 15:1995;127-136 An example of LTP-induced changes in sensory transmission in the lateral-geniculate - amygdala pathway, which is involved in fear potentiation of startle. The pathway supports electrophysiological LTP, and after LTP is induced, electrically evoked potentials are themselves potentiated. It is important to determine whether natural LTP occurs during fear-potentiated startle and whether it is dependent on NMDA-mediated LTP.
74. Cain DP, Saucier D. The neuroscience of spatial navigation: focus on behavior yields advances. Rev Neurosci. 7:1996;215-231.
75. Whishaw IQ, Cassel J-C, Jarrard LE. Rats with fimbria-fornix lesions display a place response in a swimming pool: a dissociation between getting there and knowing where. J Neurosci. 15:1995;5779-5788.