Top

Published in:

01-08-2006 | Research Article

Growth hormone replacement in hypophysectomized rats affects spatial performance and hippocampal levels of NMDA receptor subunit and PSD-95 gene transcript levels

Authors: Madeleine Le Grevès, Qin Zhou, Marita Berg, Pierre Le Grevès, Karin Fhölenhag, Bengt Meyerson, Fred Nyberg

Published in: Experimental Brain Research | Issue 2/2006

Abstract

Clinical studies have demonstrated that growth hormone (GH) promotes learning and memory processes in GH-deficient (GHD) patients. In animal studies, GH also influences the N-methyl-D-aspartate (NMDA) receptor system in the hippocampus, an essential component of long-term potentiation (LTP), which is highly involved in memory acquisition. This study was designed to examine the beneficial effects of recombinant human GH (rhGH) on cognitive function in male rats with multiple hormone deficiencies resulting from hypophysectomy (Hx). The performance of an rhGH-treated group and an untreated control group was appraised in the Morris water maze (MWM). The rhGH-treated group performed significantly better in the spatial memory task than the control animals on the second and third trial days. Further training eliminated this difference between the groups. Hippocampal mRNA expression of the NMDA subunits NR1, NR2A and NR2B, insulin-like growth factor type 1 receptor (IGF-1R), and postsynaptic density protein-95 (PSD-95) was then measured in the animals by Northern blot analysis. The results suggest that there may be a relationship between the NMDA receptor subunit mRNA expression levels and learning ability, and that learning is improved by rhGH in Hx rats. Furthermore, a link between MWM performance and PSD-95 was also suggested by this study.

Adams MM, Smith TD, Moga D, Gallagher M, Wang Y, Wolfe BB, Rapp PR, Morrison JH (2001) Hippocampal dependent learning ability correlates with N-methyl-D-aspartate (NMDA) receptor levels in CA3 neurons of young and aged rats. J Comp Neurol 432:230–243PubMedCrossRef

Albert MS, Funkenstein HH (1992) The effects of age: normal variation and its relation to disease. In: Asbury AK, McKhann GM, McDonald WI (eds) Diseases of the nervous system: clinical neurobiology. W.B. Saunders, Philadelphia

Barnes CA (1979) Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. J Comp Physiol Psychol 93:74–104PubMedCrossRef

Bengtsson BA, Eden S, Lönn L, Kvist H, Stokland A, Lindstedt G, Bosaeus I, Tolli J, Sjöström L, Isaksson OG (1993) Treatment of adults with growth hormone (GH) deficiency with recombinant human GH. J Clin Endocrinol Metab 76:309–317PubMedCrossRef

Blackstone C, Sheng M (1999) Protein targeting and calcium signaling microdomains in neuronal cells. Cell Calcium 26:181–192PubMedCrossRef

Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39PubMedCrossRef

Burman P, Deijen JB (1998) Quality of life and cognitive function in patients with pituitary insufficiency. Psychother Psychosom 67:154–167PubMedCrossRef

Burman P, Broman JE, Hetta J, Wiklund I, Erfurth EM, Hägg E, Karlsson FA (1995) Quality of life in adults with growth hormone (GH) deficiency: response to treatment with recombinant human GH in a placebo-controlled 21-month trial. J Clin Endocrinol Metab 80:3585–3590PubMedCrossRef

Carroll PV, Christ ER, Sonksen PH (2000) Growth hormone replacement in adults with growth hormone deficiency: assessment of current knowledge. Trends Endocrinol Metab 11:231–238PubMedCrossRef

Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159PubMedCrossRef

Clayton DA, Mesches MH, Alvarez E, Bickford PC, Browning MD (2002) A hippocampal NR2B deficit can mimic age-related changes in long-term potentiation and spatial learning in the Fischer 344 rat. J Neurosci 22:3628–3637PubMed

Collingridge G (1987) Synaptic plasticity. The role of NMDA receptors in learning and memory. Nature 330:604–605PubMedCrossRef

Crusio WE, Schwegler H (1987) Hippocampal mossy fiber distribution covaries with open-field habituation in the mouse. Behav Brain Res 26:153–158PubMedCrossRef

Crusio WE, Schwegler H, Lipp HP (1987) Radial-maze performance and structural variation of the hippocampus in mice: a correlation with mossy fibre distribution. Brain Res 425:182–185PubMedCrossRef

Deijen JB, de Boer H, van der Veen EA (1998) Cognitive changes during growth hormone replacement in adult men. Psychoneuroendocrinology 23:45–55PubMedCrossRef

Dik MG, Pluijm SM, Jonker C, Deeg DJ, Lomecky MZ, Lips P (2003) Insulin-like growth factor I (IGF-I) and cognitive decline in older persons. Neurobiol Aging 24:573–581PubMedCrossRef

Driscoll I, Hamilton DA, Petropoulos H, Yeo RA, Brooks WM, Baumgartner RN, Sutherland RJ (2003) The aging hippocampus: cognitive, biochemical and structural findings. Cereb Cortex 13:1344–1351PubMedCrossRef

Fagiolini M, Katagiri H, Miyamoto H, Mori H, Grant SG, Mishina M, Hensch TK (2003) Separable features of visual cortical plasticity revealed by N-methyl-D-aspartate receptor 2A signaling. Proc Natl Acad Sci USA 100:2854–2859PubMedCrossRef

Florini JR, Roberts SB (1980) Effect of rat age on blood levels of somatomedin-like growth factors. J Gerontol 35:23–30PubMed

Garner CC, Nash J, Huganir RL (2000) PDZ domains in synapse assembly and signalling. Trends Cell Biol 10:274–280PubMedCrossRef

Gibney J, Wallace JD, Spinks T, Schnorr L, Ranicar A, Cuneo RC, Lockhart S, Burnand KG, Salomon F, Sonksen PH, Russell-Jones D (1999) The effects of 10 years of recombinant human growth hormone (GH) in adult GH-deficient patients. J Clin Endocrinol Metab 84:2596–2602PubMedCrossRef

Hunt CA, Schenker LJ, Kennedy MB (1996) PSD-95 is associated with the postsynaptic density and not with the presynaptic membrane at forebrain synapses. J Neurosci 16:1380–1388PubMed

Husi H, Ward MA, Choudhary JS, Blackstock WP, Grant SG (2000) Proteomic analysis of NMDA receptor-adhesion protein signaling complexes. Nat Neurosci 3:661–669PubMedCrossRef

Ingram DK, Shimada A, Spangler EL, Ikari H, Hengemihle J, Kuo H, Greig N (1996) Cognitive enhancement. New strategies for stimulating cholinergic, glutamatergic, and nitric oxide systems. Ann N Y Acad Sci 786:348–361PubMedCrossRef

Jacobs LF, Gaulin SJ, Sherry DF, Hoffman GE (1990) Evolution of spatial cognition: sex-specific patterns of spatial behavior predict hippocampal size. Proc Natl Acad Sci USA 87:6349–6352PubMedCrossRef

Kornau HC, Schenker LT, Kennedy MB, Seeburg PH (1995) Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science 269:1737–1740PubMedCrossRef

Lamberts SW, van den Beld AW, van der Lely AJ (1997) The endocrinology of aging. Science 278:419–424PubMedCrossRef

Le Grevès M, Fhölenhag K, Zhou Q, Berg M, Meyerson B, Nyberg F (2000) Effects of recombinant human growth hormone on learning and memory function. Growth Horm IGF Res 10:130

Le Grevès M, Steensland P, Le Grevès P, Nyberg F (2002) Growth hormone induces age-dependent alteration in the expression of hippocampal growth hormone receptor and N-methyl-D-aspartate receptor subunits gene transcripts in male rats. Proc Natl Acad Sci USA 99:7119–7123PubMedCrossRef

Le Grevès M, Le Grevès P, Nyberg F (2005) Age-related effects of IGF-1 on the NMDA-, GH- and IGF-1-receptor mRNA transcripts in the rat hippocampus. Brain Res Bull 65:369–374PubMedCrossRef

Lipp HP, Schwegler H, Heimrich B, Cerbone A, Sadile AG (1987) Strain-specific correlations between hippocampal structural traits and habituation in a spatial novelty situation. Behav Brain Res 24:111–123PubMedCrossRef

Liu L, Wong TP, Pozza MF, Lingenhoehl K, Wang Y, Sheng M, Auberson YP, Wang YT (2004) Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science 304:1021–1024PubMedCrossRef

Markowska AL, Mooney M, Sonntag WE (1998) Insulin-like growth factor-1 ameliorates age-related behavioral deficits. Neuroscience 87:559–569PubMedCrossRef

McGauley GA, Cuneo RC, Salomon F, Sonksen PH (1990) Psychological well-being before and after growth hormone treatment in adults with growth hormone deficiency. Horm Res 33:52–54PubMedCrossRef

Migaud M, Charlesworth P, Dempster M, Webster LC, Watabe AM, Makhinson M, He Y, Ramsay MF, Morris RG, Morrison JH, O’Dell TJ, Grant SG (1998) Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature 396:433–439PubMedCrossRef

Monyer H, Sprengel R, Schoepfer R, Herb A, Higuchi M, Lomeli H, Burnashev N, Sakmann B, Seeburg PH (1992) Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science 256:1217–1221PubMedCrossRef

Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH (1994) Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12:529–540PubMedCrossRef

Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11:47–60PubMedCrossRef

Morris RG, Garrud P, Rawlins JN, O’Keefe J (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297:681–683PubMedCrossRef

Muller BM, Kistner U, Kindler S, Chung WJ, Kuhlendahl S, Fenster SD, Lau LF, Veh RW, Huganir RL, Gundelfinger ED, Garner CC (1996) SAP102, a novel postsynaptic protein that interacts with NMDA receptor complexes in vivo. Neuron 17:255–265PubMedCrossRef

Nakanishi S (1992) Molecular diversity of glutamate receptors and implications for brain function. Science 258:597–603PubMedCrossRef

Nicolle MM, Prescott S, Bizon JL (2003) Emergence of a cue strategy preference on the water maze task in aged C57B6 x SJL F1 hybrid mice. Learn Mem 10:520–524PubMedCrossRef

Nyberg F (2000) Growth hormone in the brain: characteristics of specific brain targets for the hormone and their functional significance. Front Neuroendocrinol 21:330–348PubMedCrossRef

O’Brien RJ, Lau LF, Huganir RL (1998) Molecular mechanisms of glutamate receptor clustering at excitatory synapses. Curr Opin Neurobiol 8:364–369PubMedCrossRef

Ramsey MM, Weiner JL, Moore TP, Carter CS, Sonntag WE (2004) Growth hormone treatment attenuates age-related changes in hippocampal short-term plasticity and spatial learning. Neuroscience 129:119–127PubMedCrossRef

Sakimura K, Kutsuwada T, Ito I, Manabe T, Takayama C, Kushiya E, Yagi T, Aizawa S, Inoue Y, Sugiyama H et al (1995) Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor epsilon 1 subunit. Nature 373:151–155PubMedCrossRef

Schneider-Rivas S, Rivas-Arancibia S, Vazquez-Pereyra F, Vazquez-Sandoval R, Borgonio-Perez G (1995) Modulation of long-term memory and extinction responses induced by growth hormone (GH) and growth hormone releasing hormone (GHRH) in rats. Life Sci 56:L433–441CrossRef

Scoville WB, Milner B (1957) Loss of recent memory after bilateral hippocampal lesions. J Neurochem 20:11–21

Sheng M (2001) Molecular organization of the postsynaptic specialization. Proc Natl Acad Sci USA 98:7058–7061PubMedCrossRef

Soares CN, Musolino NR, Cunha Neto M, Caires MA, Rosenthal MC, Camargo CP, Bronstein MD (1999) Impact of recombinant human growth hormone (RH-GH) treatment on psychiatric, neuropsychological and clinical profiles of GH deficient adults A placebo-controlled trial. Arq Neuropsiquiatr 57:182–189PubMed

Sonntag WE, Bennett SA, Khan AS, Thornton PL, Xu X, Ingram RL, Brunso-Bechtold JK (2000) Age and insulin-like growth factor-1 modulate N-methyl-D-aspartate receptor subtype expression in rats. Brain Res Bull 51:331–338PubMedCrossRef

Sprengel R, Suchanek B, Amico C, Brusa R, Burnashev N, Rozov A, Hvalby O, Jensen V, Paulsen O, Andersen P, Kim JJ, Thompson RF, Sun W, Webster LC, Grant SG, Eilers J, Konnerth A, Li J, McNamara JO, Seeburg PH (1998) Importance of the intracellular domain of NR2 subunits for NMDA receptor function in vivo. Cell 92:279–289PubMedCrossRef

Stenvers KL, Lund PK, Gallagher M (1996) Increased expression of type 1 insulin-like growth factor receptor messenger RNA in rat hippocampal formation is associated with aging and behavioral impairment. Neuroscience 72:505–518PubMedCrossRef

Sutherland RJ, Kolb B, Whishaw IQ (1982) Spatial mapping: definitive disruption by hippocampal or medial frontal cortical damage in the rat. Neurosci Lett 31:271–276PubMedCrossRef

Tang YP, Shimizu E, Dube GR, Rampon C, Kerchner GA, Zhuo M, Liu G, Tsien JZ (1999) Genetic enhancement of learning and memory in mice. Nature 401:63–69PubMedCrossRef

Thornton PL, Ingram RL, Sonntag WE (2000) Chronic [D-Ala²]-growth hormone-releasing hormone administration attenuates age-related deficits in spatial memory. J Gerontol A Biol Sci Med Sci 55:B106–112PubMed

Tovar KR, Westbrook GL (1999) The incorporation of NMDA receptors with a distinct subunit composition at nascent hippocampal synapses in vitro. J Neurosci 19:4180–4188PubMed

Tsien JZ, Huerta PT, Tonegawa S (1996) The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell 87:1327–1338PubMedCrossRef

Vaynman S, Ying Z, Gomez-Pinilla F (2004) Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci 20:2580–2590PubMedCrossRef

Walikonis RS, Jensen ON, Mann M, Provance DW Jr, Mercer JA, Kennedy MB (2000) Identification of proteins in the postsynaptic density fraction by mass spectrometry. J Neurosci 20:4069–4080PubMed

Watanabe M, Inoue Y, Sakimura K, Mishina M (1992) Developmental changes in distribution of NMDA receptor channel subunit mRNAs. Neuroreport 3:1138–1140PubMedCrossRef

Williams JM, Guevremont D, Kennard JT, Mason-Parker SE, Tate WP, Abraham WC (2003) Long-term regulation of N-methyl-D-aspartate receptor subunits and associated synaptic proteins following hippocampal synaptic plasticity. Neuroscience 118:1003–1013PubMedCrossRef

Wirén L, Bengtsson BA, Johannsson G (1998) Beneficial effects of long-term GH replacement therapy on quality of life in adults with GH deficiency (Oxf). Clin Endocrinol 48:613–620CrossRef

Title: Growth hormone replacement in hypophysectomized rats affects spatial performance and hippocampal levels of NMDA receptor subunit and PSD-95 gene transcript levels
Authors: Madeleine Le Grevès
Qin Zhou
Marita Berg
Pierre Le Grevès
Karin Fhölenhag
Bengt Meyerson
Fred Nyberg
Publication date: 01-08-2006
Publisher: Springer-Verlag
Published in: Experimental Brain Research / Issue 2/2006
Print ISSN: 0014-4819
Electronic ISSN: 1432-1106
DOI: https://doi.org/10.1007/s00221-006-0438-2

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Growth hormone replacement in hypophysectomized rats affects spatial performance and hippocampal levels of NMDA receptor subunit and PSD-95 gene transcript levels

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2006

The impact of restricted diet on brain function using BOLD-fMRI

Immunoreactivities to protein gene product 9.5, neurofilament protein and neuron specific enolase in the ovary of the sexually immature ostrich (Struthio camelus)

Prenatal and postnatal maternal contributions in the infection model of schizophrenia

Modulation of sympathetic neurotransmission by neuropeptide Y Y2 receptors in rats and guinea pigs

Mitochondrial dysmorphology in the neuroepithelium of rat embryos following a single dose of maternal hyperthermia during gestation

Parkinson’s disease: a rethink of rodent models