Top

Published in:

Open Access 01-12-2014 | Research

Enhanced stability of hippocampal place representation caused by reduced magnesium block of NMDA receptors in the dentate gyrus

Authors: Yuichiro Hayashi, Yoko Nabeshima, Katsunori Kobayashi, Tsuyoshi Miyakawa, Koichi Tanda, Keizo Takao, Hidenori Suzuki, Eisaku Esumi, Shigeru Noguchi, Yukiko Matsuda, Toshikuni Sasaoka, Tetsuo Noda, Jun-ichi Miyazaki, Masayoshi Mishina, Kazuo Funabiki, Yo-ichi Nabeshima

Published in: Molecular Brain | Issue 1/2014

Abstract

Background

Voltage-dependent block of the NMDA receptor by Mg²⁺ is thought to be central to the unique involvement of this receptor in higher brain functions. However, the in vivo role of the Mg²⁺ block in the mammalian brain has not yet been investigated, because brain-wide loss of the Mg²⁺ block causes perinatal lethality. In this study, we used a brain-region specific knock-in mouse expressing an NMDA receptor that is defective for the Mg²⁺ block in order to test its role in neural information processing.

Results

We devised a method to induce a single amino acid substitution (N595Q) in the GluN2A subunit of the NMDA receptor, specifically in the hippocampal dentate gyrus in mice. This mutation reduced the Mg²⁺ block at the medial perforant path–granule cell synapse and facilitated synaptic potentiation induced by high-frequency stimulation. The mutants had more stable hippocampal place fields in the CA1 than the controls did, and place representation showed lower sensitivity to visual differences. In addition, behavioral tests revealed that the mutants had a spatial working memory deficit.

Conclusions

These results suggest that the Mg²⁺ block in the dentate gyrus regulates hippocampal spatial information processing by attenuating activity-dependent synaptic potentiation in the dentate gyrus.

Available only for authorised users

Nakanishi S, Nakajima Y, Masu M, Ueda Y, Nakahara K, Watanabe D, Yamaguchi S, Kawabata S, Okada M: Glutamate receptors: brain function and signal transduction. Brain Res Brain Res Rev. 1998, 26: 230-235. 10.1016/S0165-0173(97)00033-7.PubMedCrossRef

Mayer ML, Westbrook GL, Guthrie PB: Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature. 1984, 309: 261-263. 10.1038/309261a0.PubMedCrossRef

Nowak L, Bregestovski P, Ascher P, Herbet A, Prochiantz A: Magnesium gates glutamate-activated channels in mouse central neurones. Nature. 1984, 307: 462-465. 10.1038/307462a0.PubMedCrossRef

Bliss TV, Collingridge GL: A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993, 361: 31-39. 10.1038/361031a0.PubMedCrossRef

Rezvani AH: Involvement of the NMDA System in Learning and Memory. Animal Models of Cognitive Impairment. Edited by: Levin ED, Buccafusco JJ. 2006, Boca Raton (FL): CRC Press

Slutsky I, Abumaria N, Wu LJ, Huang C, Zhang L, Li B, Zhao X, Govindarajan A, Zhao MG, Zhuo M, Tonegawa S, Liu G: Enhancement of learning and memory by elevating brain magnesium. Neuron. 2010, 65: 165-177. 10.1016/j.neuron.2009.12.026.PubMedCrossRef

Miyashita T, Oda Y, Horiuchi J, Yin JC, Morimoto T, Saitoe M: Mg(2+) block of Drosophila NMDA receptors is required for long-term memory formation and CREB-dependent gene expression. Neuron. 2012, 74: 887-898. 10.1016/j.neuron.2012.03.039.PubMedCrossRef

Single FN, Rozov A, Burnashev N, Zimmermann F, Hanley DF, Forrest D, Curran T, Jensen V, Hvalby O, Sprengel R, Seeburg PH: Dysfunctions in mice by NMDA receptor point mutations NR1(N598Q) and NR1(N598R). J Neurosci. 2000, 20: 2558-2566.PubMed

Burnashev N, Schoepfer R, Monyer H, Ruppersberg JP, Gunther W, Seeburg PH, Sakmann B: Control by asparagine residues of calcium permeability and magnesium blockade in the NMDA receptor. Science. 1992, 257: 1415-1419. 10.1126/science.1382314.PubMedCrossRef

10.

Mori H, Masaki H, Yamakura T, Mishina M: Identification by mutagenesis of a Mg(2+)-block site of the NMDA receptor channel. Nature. 1992, 358: 673-675. 10.1038/358673a0.PubMedCrossRef

11.

Scoville WB, Milner B: Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry. 1957, 20: 11-21. 10.1136/jnnp.20.1.11.PubMedPubMedCentralCrossRef

12.

Morris RG, Garrud P, Rawlins JN, O'Keefe J: Place navigation impaired in rats with hippocampal lesions. Nature. 1982, 297: 681-683. 10.1038/297681a0.PubMedCrossRef

13.

Amaral DG, Witter MP: The three-dimensional organization of the hippocampal formation: a review of anatomical data. Neuroscience. 1989, 31: 571-591. 10.1016/0306-4522(89)90424-7.PubMedCrossRef

14.

O'Keefe J, Dostrovsky J: The hippocampus as a spatial map: preliminary evidence from unit activity in the freely-moving rat. Brain Res. 1971, 34: 171-175.PubMedCrossRef

15.

O'Keefe J, Nadel L: The hippocampus as a cognitive map. 1978, Oxford: Oxford University Press

16.

Wills TJ, Lever C, Cacucci F, Burgess N, O'Keefe J: Attractor dynamics in the hippocampal representation of the local environment. Science. 2005, 308: 873-876. 10.1126/science.1108905.PubMedPubMedCentralCrossRef

17.

Nakazawa K, Quirk MC, Chitwood RA, Watanabe M, Yeckel MF, Sun LD, Kato A, Carr CA, Johnston D, Wilson MA, Tonegawa S: Requirement for hippocampal CA3 NMDA receptors in associative memory recall. Science. 2002, 297: 211-218. 10.1126/science.1071795.PubMedPubMedCentralCrossRef

18.

Leutgeb JK, Leutgeb S, Moser MB, Moser EI: Pattern separation in the dentate gyrus and CA3 of the hippocampus. Science. 2007, 315: 961-966. 10.1126/science.1135801.PubMedCrossRef

19.

Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH: Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron. 1994, 12: 529-540. 10.1016/0896-6273(94)90210-0.PubMedCrossRef

20.

Smith CW, Nadal-Ginard B: Mutually exclusive splicing of alpha-tropomyosin exons enforced by an unusual lariat branch point location: implications for constitutive splicing. Cell. 1989, 56: 749-758. 10.1016/0092-8674(89)90678-8.PubMedCrossRef

21.

Zhang XM, Ng AH, Tanner JA, Wu WT, Copeland NG, Jenkins NA, Huang JD: Highly restricted expression of Cre recombinase in cerebellar Purkinje cells. Genesis. 2004, 40: 45-51. 10.1002/gene.20062.PubMedCrossRef

22.

Hanse E, Gustafsson B: Long-term potentiation and field EPSPs in the lateral and medial perforant paths in the dentate gyrus in Vitro: a comparison. Eur J Neurosci. 1992, 4: 1191-1201. 10.1111/j.1460-9568.1992.tb00144.x.PubMedCrossRef

23.

Wigstrom H, Gustafsson B: Large long-lasting potentiation in the dentate gyrus in vitro during blockade of inhibition. Brain Res. 1983, 275: 153-158. 10.1016/0006-8993(83)90428-6.PubMedCrossRef

24.

McNaughton BL, Barnes CA, O'Keefe J: The contributions of position, direction, and velocity to single unit activity in the hippocampus of freely-moving rats. Exp Brain Res. 1983, 52: 41-49.PubMedCrossRef

25.

Kentros C, Hargreaves E, Hawkins RD, Kandel ER, Shapiro M, Muller RV: Abolition of long-term stability of new hippocampal place cell maps by NMDA receptor blockade. Science. 1998, 280: 2121-2126. 10.1126/science.280.5372.2121.PubMedCrossRef

26.

Fenton AA, Muller RU: Place cell discharge is extremely variable during individual passes of the rat through the firing field. Proc Natl Acad Sci U S A. 1998, 95: 3182-3187. 10.1073/pnas.95.6.3182.PubMedPubMedCentralCrossRef

27.

Kentros CG, Agnihotri NT, Streater S, Hawkins RD, Kandel ER: Increased attention to spatial context increases both place field stability and spatial memory. Neuron. 2004, 42: 283-295. 10.1016/S0896-6273(04)00192-8.PubMedCrossRef

28.

Cho YH, Giese KP, Tanila H, Silva AJ, Eichenbaum H: Abnormal hippocampal spatial representations in alphaCaMKIIT286A and CREBalphaDelta- mice. Science. 1998, 279: 867-869. 10.1126/science.279.5352.867.PubMedCrossRef

29.

Altman J, Das GD: Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol. 1965, 124: 319-335. 10.1002/cne.901240303.PubMedCrossRef

30.

Clelland CD, Choi M, Romberg C, Clemenson GD, Fragniere A, Tyers P, Jessberger S, Saksida LM, Barker RA, Gage FH, Bussey TJ: A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science. 2009, 325: 210-213. 10.1126/science.1173215.PubMedPubMedCentralCrossRef

31.

Sahay A, Scobie KN, Hill AS, O'Carroll CM, Kheirbek MA, Burghardt NS, Fenton AA, Dranovsky A, Hen R: Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature. 2011, 472: 466-470. 10.1038/nature09817.PubMedPubMedCentralCrossRef

32.

Nakashiba T, Cushman JD, Pelkey KA, Renaudineau S, Buhl DL, McHugh TJ, Rodriguez Barrera V, Chittajallu R, Iwamoto KS, McBain CJ, Fanselow MS, Tonegawa S: Young dentate granule cells mediate pattern separation, whereas old granule cells facilitate pattern completion. Cell. 2012, 149: 188-201. 10.1016/j.cell.2012.01.046.PubMedPubMedCentralCrossRef

33.

Tashiro A, Sandler VM, Toni N, Zhao C, Gage FH: NMDA-receptor-mediated, cell-specific integration of new neurons in adult dentate gyrus. Nature. 2006, 442: 929-933. 10.1038/nature05028.PubMedCrossRef

34.

Furukawa H, Singh SK, Mancusso R, Gouaux E: Subunit arrangement and function in NMDA receptors. Nature. 2005, 438: 185-192. 10.1038/nature04089.PubMedCrossRef

35.

Seeburg PH, Single F, Kuner T, Higuchi M, Sprengel R: Genetic manipulation of key determinants of ion flow in glutamate receptor channels in the mouse. Brain Res. 2001, 907: 233-243. 10.1016/S0006-8993(01)02445-3.PubMedCrossRef

36.

Slutsky I, Sadeghpour S, Li B, Liu G: Enhancement of synaptic plasticity through chronically reduced Ca2+ flux during uncorrelated activity. Neuron. 2004, 44: 835-849. 10.1016/j.neuron.2004.11.013.PubMedCrossRef

37.

McNaughton BL, Barnes CA, Meltzer J, Sutherland RJ: Hippocampal granule cells are necessary for normal spatial learning but not for spatially-selective pyramidal cell discharge. Exp Brain Res. 1989, 76: 485-496. 10.1007/BF00248904.PubMedCrossRef

38.

Thompson LT, Best PJ: Place cells and silent cells in the hippocampus of freely-behaving rats. J Neurosci. 1989, 9: 2382-2390.PubMed

39.

O'Reilly RC, McClelland JL: Hippocampal conjunctive encoding, storage, and recall: avoiding a trade-off. Hippocampus. 1994, 4: 661-682. 10.1002/hipo.450040605.PubMedCrossRef

40.

McHugh TJ, Jones MW, Quinn JJ, Balthasar N, Coppari R, Elmquist JK, Lowell BB, Fanselow MS, Wilson MA, Tonegawa S: Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network. Science. 2007, 317: 94-99. 10.1126/science.1140263.PubMedCrossRef

41.

Johnston D, Amaral DG: Hippocampus. The synaptic organization of the brain. Edited by: Sheperd GM. 1998, Oxford: Oxford University Press, 417-458.

42.

Perkel DJ, Hestrin S, Sah P, Nicoll RA: Excitatory synaptic currents in Purkinje cells. Proc Biol Sci. 1990, 241: 116-121. 10.1098/rspb.1990.0074.PubMedCrossRef

43.

Llano I, Marty A, Armstrong CM, Konnerth A: Synaptic- and agonist-induced excitatory currents of Purkinje cells in rat cerebellar slices. J Physiol. 1991, 434: 183-213.PubMedPubMedCentralCrossRef

44.

Piochon C, Levenes C, Ohtsuki G, Hansel C: Purkinje cell NMDA receptors assume a key role in synaptic gain control in the mature cerebellum. J Neurosci. 2010, 30: 15330-15335. 10.1523/JNEUROSCI.4344-10.2010.PubMedPubMedCentralCrossRef

45.

Yakusheva TA, Shaikh AG, Green AM, Blazquez PM, Dickman JD, Angelaki DE: Purkinje cells in posterior cerebellar vermis encode motion in an inertial reference frame. Neuron. 2007, 54: 973-985. 10.1016/j.neuron.2007.06.003.PubMedCrossRef

46.

Angelaki DE, Yakusheva TA, Green AM, Dickman JD, Blazquez PM: Computation of egomotion in the macaque cerebellar vermis. Cerebellum. 2010, 9: 174-182. 10.1007/s12311-009-0147-z.PubMedPubMedCentralCrossRef

47.

Rochefort C, Arabo A, Andre M, Poucet B, Save E, Rondi-Reig L: Cerebellum shapes hippocampal spatial code. Science. 2011, 334: 385-389. 10.1126/science.1207403.PubMedCrossRef

48.

Muller RU, Kubie JL: The effects of changes in the environment on the spatial firing of hippocampal complex-spike cells. J Neurosci. 1987, 7: 1951-1968.PubMed

49.

Treves A, Rolls ET: Computational constraints suggest the need for two distinct input systems to the hippocampal CA3 network. Hippocampus. 1992, 2: 189-199. 10.1002/hipo.450020209.PubMedCrossRef

50.

Marr D: Simple memory: a theory for archicortex. Philos Trans R Soc Lond B Biol Sci. 1971, 262: 23-81. 10.1098/rstb.1971.0078.PubMedCrossRef

51.

Douglass JK, Wilkens L, Pantazelou E, Moss F: Noise enhancement of information transfer in crayfish mechanoreceptors by stochastic resonance. Nature. 1993, 365: 337-340. 10.1038/365337a0.PubMedCrossRef

52.

Moss F, Ward LM, Sannita WG: Stochastic resonance and sensory information processing: a tutorial and review of application. Clin Neurophysiol. 2004, 115: 267-281. 10.1016/j.clinph.2003.09.014.PubMedCrossRef

53.

Jackson J, Redish AD: Network dynamics of hippocampal cell-assemblies resemble multiple spatial maps within single tasks. Hippocampus. 2007, 17: 1209-1229. 10.1002/hipo.20359.PubMedCrossRef

54.

Rolls ET, Loh M, Deco G: An attractor hypothesis of obsessive-compulsive disorder. Eur J Neurosci. 2008, 28: 782-793. 10.1111/j.1460-9568.2008.06379.x.PubMedCrossRef

55.

Jackson MB, Scharfman HE: Positive feedback from hilar mossy cells to granule cells in the dentate gyrus revealed by voltage-sensitive dye and microelectrode recording. J Neurophysiol. 1996, 76: 601-616.PubMed

56.

Gage FH: Neurogenesis in the adult brain. J Neurosci. 2002, 22: 612-613.PubMed

57.

Meguro H, Mori H, Araki K, Kushiya E, Kutsuwada T, Yamazaki M, Kumanishi T, Arakawa M, Sakimura K, Mishina M: Functional characterization of a heteromeric NMDA receptor channel expressed from cloned cDNAs. Nature. 1992, 357: 70-74. 10.1038/357070a0.PubMedCrossRef

58.

Boggs RT, Gregor P, Idriss S, Belote JM, McKeown M: Regulation of sexual differentiation in D melanogaster via alternative splicing of RNA from the transformer gene. Cell. 1987, 50: 739-747. 10.1016/0092-8674(87)90332-1.PubMedCrossRef

59.

Yagi T, Tokunaga T, Furuta Y, Nada S, Yoshida M, Tsukada T, Saga Y, Takeda N, Ikawa Y, Aizawa S: A novel ES cell line, TT2, with high germline-differentiating potency. Anal Biochem. 1993, 214: 70-76. 10.1006/abio.1993.1458.PubMedCrossRef

60.

Imai F, Hirai S, Akimoto K, Koyama H, Miyata T, Ogawa M, Noguchi S, Sasaoka T, Noda T, Ohno S: Inactivation of aPKClambda results in the loss of adherens junctions in neuroepithelial cells without affecting neurogenesis in mouse neocortex. Development. 2006, 133: 1735-1744. 10.1242/dev.02330.PubMedCrossRef

61.

Araki K, Araki M, Miyazaki J, Vassalli P: Site-specific recombination of a transgene in fertilized eggs by transient expression of Cre recombinase. Proc Natl Acad Sci U S A. 1995, 92: 160-164. 10.1073/pnas.92.1.160.PubMedPubMedCentralCrossRef

62.

Miyakawa T, Yared E, Pak JH, Huang FL, Huang KP, Crawley JN: Neurogranin null mutant mice display performance deficits on spatial learning tasks with anxiety related components. Hippocampus. 2001, 11: 763-775. 10.1002/hipo.1092.PubMedCrossRef

63.

Fox SE, Ranck JB: Localization and anatomical identification of theta and complex spike cells in dorsal hippocampal formation of rats. Exp Neurol. 1975, 49: 299-313. 10.1016/0014-4886(75)90213-7.PubMedCrossRef

64.

Fox SE, Ranck JB: Electrophysiological characteristics of hippocampal complex-spike cells and theta cells. Exp Brain Res. 1981, 41: 399-410.PubMed

65.

Harris KD, Henze DA, Csicsvari J, Hirase H, Buzsaki G: Accuracy of tetrode spike separation as determined by simultaneous intracellular and extracellular measurements. J Neurophysiol. 2000, 84: 401-414.PubMed

66.

Hazan L, Zugaro M, Buzsaki G: Klusters, NeuroScope, NDManager: a free software suite for neurophysiological data processing and visualization. J Neurosci Methods. 2006, 155: 207-216. 10.1016/j.jneumeth.2006.01.017.PubMedCrossRef

Title: Enhanced stability of hippocampal place representation caused by reduced magnesium block of NMDA receptors in the dentate gyrus
Authors: Yuichiro Hayashi
Yoko Nabeshima
Katsunori Kobayashi
Tsuyoshi Miyakawa
Koichi Tanda
Keizo Takao
Hidenori Suzuki
Eisaku Esumi
Shigeru Noguchi
Yukiko Matsuda
Toshikuni Sasaoka
Tetsuo Noda
Jun-ichi Miyazaki
Masayoshi Mishina
Kazuo Funabiki
Yo-ichi Nabeshima
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: Molecular Brain / Issue 1/2014
Electronic ISSN: 1756-6606
DOI: https://doi.org/10.1186/1756-6606-7-44

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Enhanced stability of hippocampal place representation caused by reduced magnesium block of NMDA receptors in the dentate gyrus

Abstract

Background

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2014

Role of adult neurogenesis in hippocampal-cortical memory consolidation

5-mehtyltetrahydrofolate rescues alcohol-induced neural crest cell migration abnormalities

Histamine impairs midbrain dopaminergic development in vivo by activating histamine type 1 receptors

Common strength and localization of spontaneous and evoked synaptic vesicle release sites

Zinc transporter-1 concentrates at the postsynaptic density of hippocampal synapses

TWIK-1 contributes to the intrinsic excitability of dentate granule cells in mouse hippocampus