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Research Centre for Endocrinology and Metabolism, Department of Internal Medicine, Gröna Stråket 8, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden
1 Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
2 Department of Pharmacology, Göteborg University, Göteborg, Sweden
3 Department of Psychology, Göteborg University, Göteborg, Sweden
(Requests for offprints should be addressed to J Svensson; Email: johan.svensson{at}medic.gu.se)
Conflicts of interest
O I is a co-founder of Tercica Inc, a company that produces IGF-I for use in children of short stature. No other author has any conflict of interest that would prejudice the impartiality of this scientific work.
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Abstract |
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Introduction |
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Insulin-like growth factor-I (IGF-I) is a neuroprotective hormone. IGF-I protects neurones against the toxic effects of Aß (Niikura et al. 2001), and circulating IGF-I increases the clearance of Aß from the brain (Carro et al. 2002). Furthermore, circulating IGF-I can reach the brain (Reinhardt & Bondy 1994), and may mediate the beneficial effects of exercise on the function of the central nervous system (Carro et al. 2000, 2001, Trejo et al. 2001). Systemic pharmacological IGF-I treatment increases neurogenesis and modulates neurone excitability (Aberg et al. 2000, Carro et al. 2000, Trejo et al. 2001). Several in vitro studies have suggested that IGF-I has the direct capacity to modulate synaptic efficacy via a regulation of synapse formation, neurotransmitter release and neuronal excitability (Nilsson et al. 1988, Araujo et al. 1989, Kar et al. 1997).
The major part of serum IGF-I is liver derived (Sjögren et al. 1999, Yakar et al. 1999). The serum levels of IGF-I are mainly regulated by growth hormone (GH) (Bengtsson et al. 1993), but are also affected by other factors, such as food intake, exercise and age (Landin-Wilhelmsen et al. 1994, Kaklamani et al. 1999, Ehrnborg et al. 2003). It has been hypothesised that the age-dependent decrease in serum IGF-I levels is involved in the parallel age-dependent decrease in cognitive function (Dik et al. 2003, Trejo et al. 2004) as well as in the age-dependent increase in the incidence of AD (Amaducci & Tesco 1994, Busiguina et al. 2000). Patients with childhood-onset GH deficiency and low serum IGF-I concentration may have a cognitive disturbance (van Dam et al. 2005). In experimental animals, intracerebroventricular administration of IGF ameliorates age-related behavioural deficits (Markowska et al. 1998), and systemic IGF-I administration can improve spatial memory (Sonntag et al. 2000, 2005). However, the specific, physiological role of liver-derived endocrine IGF-I for cognitive function in ageing is unknown.
The development of a mouse model with liver-specific, inducible inactivation of the IGF-I gene, using the Cre-LoxP conditional knockout system (LI-IGF-I–/– mice) (Sjögren et al. 1999, 2001, 2002, Wallenius et al. 2001, Tivesten et al. 2002), has made it possible to investigate the role of liver-derived IGF-I in adult mice. These mice do not have decreased IGF-I expression in the brain (Sjögren et al. 1999, Wallenius et al. 2001). Here we have assessed the role of adult expression of liver-derived IGF-I for spatial learning and memory, and have investigated to what extent this factor influences the expression patterns of a number of neuropeptides and other molecules associated with hippocampal function.
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Materials and Methods |
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The LI-IGF-I–/– mice were generated as previously described (Sjögren et al. 1999). Mice homozygous for LoxP (Liu et al. 1998) and heterozygous for Mx-Cre (Kuhn et al. 1995) were given polyinosinic-polycytidylic acid (PiPc; 6.25 µg/g body weight; Sigma-Aldrich Corp) in three i.p. injections at 6 weeks of age (mice aged 6 or 15 months at the water maze trials) or 10 weeks of age (mice aged 18 months at the water maze trials), to induce expression of the Cre protein in the liver (Kuhn et al. 1995). PiPc-treated littermates, homozygous for LoxP but lacking Mx-Cre, were used as controls. It is more practical to inactivate liver-derived IGF-I at 6 weeks of age when the mice are smaller and require a lower dose of PiPc. However, pre- and postnatal IGF-I expression is important for the development of the brain, and to definitely confirm that there was no interference with brain development, the LI-IGF-I–/– mice aged 18 months at the water maze trials were inactivated at 10 weeks of age.
Seven days after the first PiPc injection, blood was collected, and serum was assayed for IGF-I by a double-antibody IGF-binding protein-blocked RIA using a commercial kit (Mediagnost, Tubingen, Germany). In addition, in the 18-month-old mice, serum IGF-I (Mediagnost) was measured after the completion of the water maze tests. The animals had free access to fresh water and food pellets (B&K Universal AB, Sollentuna, Sweden). The study was approved by the ethical committees at the University of Göteborg and the Karolinska Institute, Stockholm, Sweden.
Water maze
Spatial learning and memory were tested in the water swim maze introduced by Morris (1981) and Morris et al.(1982). The apparatus and procedures for the determination of spatial learning and memory used in this and other studies (Sundström et al. 1988, Fredriksson et al. 2000, 2004, Archer et al. 2002) were similar, but not identical, to that originally described by Morris (1981) and Morris et al.(1982). All experiments were performed in a lighted room containing a number of two- and three-dimensional visual cues. Pool water was maintained at 24 ± 1 °C. The escape platform was submerged 1 cm below the surface of the water and hidden from sight by the use of dried milk powder. All extra maze cues were kept in a constant position through the test periods. The water maze experiments were performed, as described below, either with fixed or randomly changed release points (where the mice were let into the water).
Water maze with fixed release point (working memory) Mice were trained for 4 days (days 1–4) with five trials per day in a circular tank (95 cm in diameter; 30 cm water depth; escape platform 11 x 11 cm). The maximal swim time for each trial was 65 s followed by a 30-s rest on the platform. The mice were released from the same site during all trials on all days. One day after the last trial (day 5), additional trials were performed, with an unchanged release point but with a changed position of the escape platform. Except for the change in the position of the escape platform, the procedures during day 5 were similar to those during days 1–4. In our hands, the results during day 5, with changed position of the escape platform, have been a valid test for spatial working memory function (Sundström et al. 1988, Fredriksson et al. 2000, 2004, Archer et al. 2002).
Water maze with random shifts in release point (reference memory) Mice were trained for 5 days (days 1–5), with four trials per day, in a circular water tank (140 cm wide; 30 cm deep; 10 cm wide escape platform). The maximal swim time for each trial was 90 s followed by a 20-s rest on the platform. The four starting points were randomised for each day of training. Reference memory test (probe trial) was performed in the absence of the platform 1 day after the last trial (day 6). During the reference memory test, each animal was released from the position opposite to the target quadrant and allowed to swim for 60 s.
Video equipment
The latency to reach the platform, swim speed, distance and, for the reference memory tests, time spent in the different quadrants, were registered with a digital camera system connected to a PC computer (2020 Plus Tracking System; HVS Image, Bristol, UK).
Immunohistochemistry
For immunohistochemistry, brains from 22-month-old female LI-IGF-I–/– and control mice were used. The mice that were killed were randomly selected from the mice aged 18 months at the water maze tests. Coronal sections (14 µm thick) of formalin–picric acid perfusion-fixed brains were cut at the level of the hippocampus, and the sections were processed for the tyramide signal amplification immunohistochemical method (Adams 1992) as described earlier (Diez et al. 2000). The sections were incubated with the following primary antisera/antibodies: (1) rabbit anti-enkephalin antiserum (1:4000) (Schultzberg et al. 1979); (2) rabbit anti-dynorphin antiserum (1:4000) (Weber et al. 1982a,b); (3) rabbit anti-glial fibrillary acidic protein (anti-GFAP) (1:8000) (Sigma-Aldrich Corp); (4) rabbit anti-zinc transporter 3 (anti-ZnT3) (1:400) (Palmiter et al. 1996); (5) sheep anti-neuronal nitric oxide synthase (anti-nNOS) (1:20 000) (Herbison et al. 1996); (6) rabbit anti-metabotropic glutamate receptor 7a (anti-mGlutR7a) (1:4000) (Shigemoto et al. 1996); and (7) serotonin (1:8000) (Verhofstad et al. 1983).
In situ hybridisation
Brains from 22-month-old female LI-IGF-I–/– (n=4) and control (n=4) mice were used for in situ hybridisation. The mice were randomly selected from the mice aged 18 months at the water maze tests. The animals were killed by decapitation and the brains quickly removed. Fresh frozen tissue was sectioned at the level of the dorsal hippocampus and hybridised with synthetic oligo-nucleotide probes with sequences complementary to mouse enkephalin mRNA (nt 255–299) (Kurawski et al. 1986) and rat dynorphin mRNA (nt 871–918) (Civelli et al. 1985). Probe labelling, in situ hybridisation and control experiments were performed according to previous published procedures (Dagerlind et al. 1992). The data were analysed using NIH Image 1.62 software (http://rsb.info.nih.gov/nih-image). Measurements were performed on three adjacent sections on the left and right hemisphere for every region studied, and a mean value thereof calculated for every animal.
Statistical analyses
All the descriptive statistical results are presented as the means ± S.E.M. (water maze) or the means ± S.D. (in situ hybridisation). Within-group differences were calculated using paired t-tests, and between-group differences were calculated using unpaired t-tests. For variables determined days 1–4 or days 1–5 during the water maze tests with fixed or randomised release points respectively, a two-way ANOVA for repeated measurement were performed, with group and time as the independent variables. Post hoc analyses were then performed using the Student–Newman–Keul’s test. A two-tailed P < 0.05 was considered significant.
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Results |
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To avoid interference with brain development, LI-IGF-I–/– mice were inactivated after sexual maturation at 6–10 weeks of age. This complete and selective IGF-I inactivation in the liver of LI-IGF-I–/– mice was associated with a 78–85% reduction in circulating IGF-I (1 week after the inactivation serum IGF-I level was 61 ± 3 ng/ml in the LI-IGF-I–/– mice and 279 ± 14 ng/ml in the control mice aged 6 months at the water maze trials, P < 0.001; 54 ± 3 ng/ml in the LI-IGF-I–/– mice and 267 ± 19 ng/ml in the control mice aged 15 months at the water maze trials, P < 0.001; and 68 ± 3 ng/ml in the LI-IGF-I–/– mice and 439 ± 22 ng/ml in the control mice aged 18 months at the water maze trials, P < 0.001). After the water maze trials were completed, serum IGF-I level was 33 ± 3 ng/ml in the 18-month-old LI-IGF-I–/– mice and 383 ± 48 ng/ml in the 18-month-old control mice, P < 0.001. In the 6-month-old and the 15-month-old mice, serum IGF-I was only determined 1 week after the inactivation of liver-derived IGF-I. We did not consider it necessary to repeat the serum IGF-I measurements in these mice since we have found in several previous studies that the reduction in serum IGF-I level is sustained (Sjögren et al. 1999, 2001, 2002, Wallenius et al. 2001, Tivesten et al. 2002). In addition, we have unpublished measurements in other LI-IGF-I–/– mice aged 24 months, and the reduction in serum IGF-I level is still maintained in these old mice (data not shown).
Behavioural analyses
Spatial working memory is decreased in old but not in young LI-IGF-I–/–mice
Spatial learning and working memory was first studied in 6-month-old LI-IGF-I–/– (n=20) and control (n=14) mice and in 18-month-old LI-IGF-I–/– (n=18) and control (n=20) mice using the Morris water maze swim test with a fixed release point. During the first 4 days, the escape platform had a fixed location in the water. The 6-month-old LI-IGF-I–/– and control mice had similar spatial memory learning during days 1–4 (two-way ANOVA for repeated measurements with group and time (days 1–4) as the independent variables, P=not significant; Fig. 1A
). The acquisition curves in control mice (6-month-old and 18-month-old controls) demonstrated that spatial memory learning was slower in the old controls as compared with the young controls (Fig. 1A).
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). Post hoc analyses using the Student–Newman–Keul’s test showed that the 18-month-old LI-IGF-I–/– mice had longer escape latency time than the age-matched control mice at day 2 (P < 0.05), and also tended to have a longer latency time at day 3 (P=0.08). At day 1 and day 4, there was no significant difference between the old LI-IGF-I–/– mice and the controls in escape latency (Fig. 1A).
At day 5, with an unchanged release point, but after the location of the platform had been altered, the young (6-month-old) LI-IGF-I–/– mice had similar latency to find the escape platform as the age-matched controls (Fig. 1B). In the 18-month-old mice, however, the latency to find the escape platform returned to baseline (=no training) values in the LI-IGF-I–/– mice, whereas in the control mice the latency time was similar to that during day 4 of the experiment (Fig. 1B).
Analyses of swim speed showed similar swim speeds in the 6-month-old and 18-month-old LI-IGF-I–/– mice as compared with the control mice of similar age during all the experiments using the water maze (Fig. 2).
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). Post hoc analyses using the Student–Newman–Keul’s test showed that the LI-IGF-I–/– mice had longer escape latency time than the control mice at day 5 (P < 0.01). The probe tests for reference memory showed a lower % of time spent in the trained quadrant in the LI-IGF-I–/– mice (P < 0.05; Fig. 3B). Analyses of swim speed showed similar swim speed in the 15-month-old LI-IGF-I–/– and control mice of a similar age during all the experiments using the water maze (data not shown).
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In order to characterise possible mechanisms underlying the impaired spatial learning and memory in old LI-IGF-I–/–mice, the hippocampal expression of two neuropeptides, enkephalin and dynorphin, known to be affected in different AD mouse models, was analysed in 22-month-old animals. These analyses also included GFAP, ZnT3, serotonin, nNOS and mGlutR7a.
Increased number of glial fibrillary acidic protein-immunoreactive (IR) cells
GFAP is a marker of astro-cyte accumulation and gliosis. In control mice, weak GFAP-IR cells were scattered in all layers of the hippocampal formation (Fig. 4A). In LI-IGF-I–/–mice, GFAP-IR cells were increased in number and intensity compared with controls, and they were most abundant in strata oriens, radiatum, lacunosum moleculare and in the polymorph layer of dentate gyrus (Fig. 4B). No difference was seen for GFAP-IR cells in the cortex of the two groups (data not shown).
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). A few weakly fluorescent fibres were also observed in strata oriens, moleculare and lacunosum moleculare. In the LI-IGF-I–/– mice, varying degrees of increases of enkephalin-LIR were observed in the polymorph layer among individuals (Fig. 4D). In contrast, enkephalin mRNA levels were significantly decreased in the granule cell layer of the dentate gyrus of LI-IGF-I–/– mice as compared with controls (Table 1). However, no difference in transcript levels was seen in the CA1 region of the pyramidal cell layer (Table 1).
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). There was also a staining of processes in the visual/auditory cortex (Fig. 4G). In the LI-IGF-I–/– mice, dynorphin-LIR was increased in the polymorph layer of the dentate gyrus compared with controls (Fig. 4F). dynorphin-positive processes and some dynorphin-positive neurones were observed in layer IV–V of the visual/auditory cortex of LI-IGF-I–/– mice (Fig. 4H). However, dynorphin mRNA levels were decreased in the granule cell layer (Table 1).
Unchanged ZnT3, serotonin and nNOS immuno-reactivities
The expression of ZnT3 transporter was used to visualise changes (possibly sprouting) of the mossy fibre network in the dentate gyrus (Cole et al. 1999, Saito et al. 2000). In control mice, there was a dense network of ZnT3-IR fibres in the polymorph layer and in the mossy fibres of the dentate gyrus (Fig. 4I). In LI-IGF-I–/– mice, these fibres appeared similar to those in the controls (Fig. 4J), suggesting that sprouting of mossy fibres did not occur. Immunoreactivity for two markers for messenger molecules, serotonin and nNOS, was similar in the hippocampal region in LI-IGF-I–/– and control mice (data not shown).
Possible increase in mGlutR7a-IR
In control mice, there was a dense network of mGlutR7a-IR fibres in the polymorph layer and in the mossy fibres of dentate gyrus (Fig. 4K). In LI-IGF-I–/– mice, there was a tendency to increased mGlutR7a expression in the fibres of the polymorph layer (Fig. 4 L), even though this increase varied among individuals.
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Discussion |
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Lifelong overexpression of IGF-I increases whereas inactivation of IGF-I or its receptor decreases brain size and the number of neurones (Carson et al. 1993, Dentremont et al. 1999, O’Kusky et al. 2000, Holzenberger et al. 2001, Vicario-Abejon et al. 2003). In humans, defects of IGF-I or IGF-I receptors due to gene mutations is associated with some mental retardation (Woods et al. 1996, Abuzzahab et al. 2003). Previous studies have shown that IGF-I is of importance for pre- and postnatal development of the brain, but they could not evaluate the role of IGF-I in adult animals because of the affected IGF-I activity during development. The LI-IGF-I–/– mice do not have decreased IGF-I expression in the brain (Sjögren et al. 1999, Wallenius et al. 2001) whereas the inactivation of liver-derived IGF-I at 6–10 weeks of age resulted in a marked reduction in serum IGF-I which was still maintained at 18 months of age. We can therefore exclude the possibility that the observed alterations were due to developmental changes in the brain.
The spatial acquisition process was slower in the old but not in the young LI-IGF-I–/– mice as compared with controls. Furthermore, in the 18-month-old LI-IGF-I–/– mice spatial working memory was impaired as the escape latency time in the LI-IGF-I–/– mice was longer than in the controls at day 5, after the position of the escape platform had been moved between days 4 and 5. The acquisition curve during days 1–4 (fixed release point) was not optimal in the 18-month-old control mice since, at day 4, the mean escape latency time was still over 30 s in the controls. The valid acquisition curve in the 6-month-old controls showed, however, that the suboptimal acquisition curve in the old control mice was due to the high age of the animals. Furthermore, the additional water maze tests in 15-month-old mice, which included randomised release points, demonstrated that spatial reference memory was also decreased in old LI-IGF-I–/– mice.
As discussed above, the 15- and 18-month-old but not the 6-month-old LI-IGF-I–/– mice had reduced spatial learning and memory. This suggests that deficiency of serum IGF-I results in decreased cognitive function in old but not in young mice. The further analyses showed similar swim speeds for old LI-IGF-I–/– and control mice, suggesting that the between-group differences in latency time in the old mice were not due to confounding factors such as musculo-skeletal alterations.
The hippocampal formation is of importance for performance in the water maze test, especially when the release point is randomly changed (Morris et al. 1982, O’Hooge & De Deyn 2001). We observed increased immunoreactivity, but decreased mRNA levels for both enkephalin and dynorphin in the dentate gyrus of old LI-IGF-I–/– mice, two peptides expressed in the granule cell/mossy fibre system. The interpretation of these findings is not straightforward, but intracellular accumulation of the two peptides in the mossy fibres may reflect decreased release of the peptide, probably related to reduced transcription of the two opioid peptides. Dynorphin attenuates excitatory neurotransmission and modulates long-term potentiation (Wagner et al. 1993, Weisskopf et al. 1993, Selkoe 2002), an electrophysiologi-cal correlate of synaptic plasticity. Increased dynorphin levels, as seen in the LI-IGF-I–/– mice, could therefore reflect a low synaptic activity at the mossy fibre–CA3 pyramidal neurone synapse, not requiring release of inhibitory dynorphin. Enkephalin has predominantly inhibitory effects in the hippocampus, mainly acting on inhibitory gamma-aminobutyric acid (GABA) inter-neurones (Segal 1977, Lee et al. 1980), thus causing dis-inhibition. Increase in enkephalin peptide together with decreased transcript levels in the granule cell–mossy fibre system could therefore lead to attenuated facilitatory mechanisms in the LI-IGF-I–/– mice. Taken together, the accumulation of dynorphin and enkephalin in mossy nerve endings combined with decreased mRNA levels suggest synaptic dysfunction in the hippocampus of the LI-IGF-I–/– mice. Increased dynorphin- and enkephalin-LIR has previously been observed in the mossy fibres of two AD mouse models (Diez et al. 2000, 2003), suggesting that intracellular accumulation of these peptides might be a common phenomenon in neurodegeneration.
The number and intensity of GFAP-IR cells were increased in 22-month-old LI-IGF-I–/– mice. This finding is in line with the results of a previous study (Carro et al. 2002), and suggests astrogliosis and neurodegeneration (Griffin et al. 1989, Unger 1998). Furthermore, mGlutR7a-IR was increased in the fibres of the polymorph layer of hippocampus in the LI-IGF-I–/– mice, indicating an imbalance in glutamatergic neurotransmission which is a feature described in AD and possibly involved in neurodegeneration (Selkoe 2002, Bleich et al. 2003).
Several lines of evidence indicate that synaptic dysfunction in AD is caused by diffusible oligomeric assemblies of the Aß protein (Selkoe 2002). Circulating IGF-I, at the level of the blood–brain barrier, regulates brain Aß levels by enhancing transport of Aß carrier proteins such as albumin and transthyretin into the brain (Carro et al. 2002). However, it is also clear that IGF-I crosses the blood–brain barrier (Reinhardt & Bondy 1994), that the IGF-I receptor is expressed in the brain (Bondy et al. 1992, Kar et al. 1997, D’Ercole & O’Kusky 2002) and that IGF-I has the direct capacity to modulate synaptic efficacy in several in vitro studies (Nilsson et al. 1988, Araujo et al. 1989, Kar et al. 1997). There are therefore several possibilities as to how deficiency of liver-derived, endocrine IGF-I impairs spatial memory learning and synaptic function in old mice. At the current stage of knowledge, it is difficult to establish which mechanism is of most importance.
In conclusion, old mice with liver-specific inactivation of IGF-I in young adult life display impaired spatial learning and memory associated with altered expression of hippocampal neuropeptides and some other markers consistent with synaptic dysfunction and with early signs of neurodegeneration. This observation provides further evidence that the decline in serum IGF-I with increasing age may be important for the age-related decline in memory function. The exact mechanism by which liver-derived endocrine IGF-I affects spatial learning and memory and synaptic function remains to be established however. Further studies are needed to evaluate the extent to which liver-derived endocrine IGF-I is involved in the pathogenesis of AD.
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Acknowledgements |
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References |
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|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Abuzzahab M, Schneider A, Goddard A, Grigorescu F, Lautier C, Keller E, Kiess W, Klammt J, Kratzsch J, Osgood D et al. 2003 IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. New England Journal of Medicine 349 2211–2222.
Adams J 1992 Biotin amplification of biotin and horseradish peroxidase signals in histochemical stains. Journal of Histochemistry and Cytochemistry 40 1457–1463.[Abstract]
Amaducci L & Tesco G 1994 Aging as a major risk for neurodegenerative diseases of the central nervous system. Current Opinion in Neurology 7 283–286.[Web of Science][Medline]
Araujo D, Lapchak P, Collier B, Chabot J & Quirion R 1989 Insulin-like growth factor-I (somatomedin-C) receptors in the rat brain: distribution and interaction with the hippocampal cholinergic system. Brain Research 484 130–138.[CrossRef][Web of Science][Medline]
Archer T, Palomo T & Fredriksson A 2002 Functional deficits following neonatal dopamine depletion and isolation housing: circular water maze acquisition under pre-exposure conditions and motor activity. Neurotoxicity Research 4 503–522.[CrossRef][Medline]
Bengtsson B-Å, Edén S, Lönn L, Kvist H, Stokland A, Lindstedt G, Bosaeus I, Tölli J, Sjöström L & Isaksson O 1993 Treatment of adults with growth hormone (GH) deficiency with recombinant human GH. Journal of Clinical Endocrinology and Metabolism 76 309–317.[Abstract]
Bleich S, Romer K, Wiltfang J & Kornhuber J 2003 Glutamate and the glutamate receptor system: a target for drug action. International Journal of Geriatric Psychiatry 18 (Suppl 1) S33–S40.[CrossRef][Web of Science][Medline]
Bondy C, Werner H, Roberts CJ & LeRoith D 1992 Cellular pattern of type-I insulin-like growth factor receptor gene expression during maturation of the brain: comparison with insulin-like growth factors I and II. Neuroscience 46 909–923.[CrossRef][Web of Science][Medline]
Busiguina S, Fernandez A, Barrios V, Clark R, Tolbert D, Berciano J & Torres-Aleman I 2000 Neurodegeneration is associated to changes in serum insulin-like growth factors. Neurobiology of Disease 7 657–665.[CrossRef][Web of Science][Medline]
Carro E, Nunez A, Busiguina S & Torres-Aleman I 2000 Circulating insulin-like growth factor I mediates effects of exercise on the brain. Journal of Neuroscience 20 2926–2933.
Carro E, Trejo J, Busiguina S & Torres-Aleman I 2001 Circulating insulin-like growth factor-I mediates the protective effects of physical exercise against brain insults of different etiology and anatomy. Journal of Neuroscience 21 5678–5684.
Carro E, Trejo J, Gomez-Isla T, LeRoith D & Torres-Aleman I 2002 Serum insulin-like growth factor I regulates brain amyloid-beta levels. Nature Medicine 8 1390–1397.[CrossRef][Web of Science][Medline]
Carson M, Behringer R, Brinster R & McMorris F 1993 Insulin-like growth factor I increases brain growth and central nervous system myelination in transgenic mice. Neuron 10 729–740.[CrossRef][Web of Science][Medline]
Civelli O, Douglas J, Goldstein A & Herbert E 1985 Sequence and expression of the rat prodynorphin gene. PNAS 82 4291–4295.
Cole T, Wenzel H, Kafer K, Schwartzkroin P & Palmiter R 1999 Elimination of zinc from synaptic vesicles in the intact mouse brain by disruption of the ZnT3 gene. PNAS 96 1716–1721.
Dagerlind Å, Friberg K, Bean A & Hökfelt T 1992 Sensitive mRNA detection using unfixed tissue: combined radioactive and non-radioactive in situ hybridization histochemistry. Histochemistry 98 39–49.[CrossRef][Web of Science][Medline]
Dentremont K, Ye P, D’Ercole A & O’Kusky J 1999 Increased insulin-like growth factor-I (IGF-I) expression during early postnatal development differentially increases neuron number and growth in medullary nuclei of the mouse. Brain Research. Developmental Brain Research 12 135–141.
D’Ercole A & O’Kusky J 2002 Mutant mouse models of insulin-like growth factor actions in the central nervous system. Neuropeptides 38 209–220.
Diez M, Koistinaho J, Kahn K, Games D & Hökfelt T 2000 Neuropeptides in hippocampus and cortex in transgenic mice overexpressing V717F beta-amyloid precursor protein – initial observations. Neuroscience 100 259–286.[CrossRef][Web of Science][Medline]
Diez M, Danner S, Frey P, Sommer B, Staufenbiel S, Wiederhold K-H & Hökfelt T 2003 Neuropeptide alterations in the hippocampal formation and cortex of transgenic mice overexpressing APP with the Swedish double mutation (APP23). Neurobiology of Disease 14 579–594.[CrossRef][Web of Science][Medline]
Dik M, Pluijm S, Jonker C, Deeg D, Lomecky M & Lips P 2003 Insulin-like growth factor I (IGF-I) and cognitive decline in older persons. Neurobiology of Aging 24 573–581.[CrossRef][Web of Science][Medline]
Ehrnborg C, Lange K, Dall R, Christiansen J, Lundberg P, Baxter R, Boroujerdi M, Bengtsson B, Healey M, Pentecost C et al. 2003 The growth hormone/insulin-like growth factor-I axis hormones and bone markers in elite athletes in response to a maximum exercise test. Journal of Clinical Endocrinology and Metabolism 88 394–401.
Fredriksson A, Schröder N, Eriksson P, Izquierdo I & Archer T 2000 Maze learning and motor activity deficits in adult mice induced by iron exposure during a critical postnatal period. Brain Research. Developmental Brain Research 119 65–74.[CrossRef][Medline]
Fredriksson A, Archer T, Alm H, Gordh T & Eriksson P 2004 Neurofunctional deficits and potentiated apoptosis by neonatal NMDA antagonist administration. Behavioural Brain Research 153 367–376.[CrossRef][Web of Science][Medline]
Griffin W, Stanley L, Ling C, White L, MacLeod V, Perrot L, White CL & Araoz C 1989 Brain interleukin 1 and S-100 immunoreactivity are elevated in Down’s syndrome and Alzheimer’s disease. PNAS 86 7611–7615.
Herbison A, Simonian S, Norris P & Emson P 1996 Relationship of neuronal nitric oxide synthase immunoreactivity to GnRH neurons in the ovariectomized and intact female rat. Journal of Neuroendocrinology 8 73–82.[CrossRef][Web of Science][Medline]
Holzenberger M, Hamard G, Zaoui R, Leneuve P, Ducos B, Beccavin C, Perin L & Le Bouc Y 2001 Experimental IGF-I receptor deficiency generates a sexually dimorphic pattern of organ-specific growth deficits in mice, affecting fat tissue in particular. Endocrinology 142 4469–4478.
Kaklamani V, Linos A, Kaklamani E, Markaki I, Koumataki Y & Mantzoros C 1999 Dietary fat and carbohydrates are independently associated with circulating insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 concentrations in healthy adults. Journal of Clinical Oncology 17 3291–3298.
Kar S, Seto D, Dore S, Hanisch U & Quirion R 1997 Insulin-like growth factors-I and -II differentially regulate endogenous acetylcholine release from the rat hippocampal formation. PNAS 94 14054–14059.
Kuhn R, Schwenk F, Aguet M & Rajewsky K 1995 Inducible gene targeting in mice. Science 269 1427–1429.
Kurawski G, Benedik M, Kamb B, Abrams J, Zurawski S & Lee F 1986 Activation of mouse T-helper cells induces abundant preproenkephalin mRNA synthesis. Science 232 772–775.
Landin-Wilhelmsen K, Wilhelmsen L, Lappas G, Rosén T, Lindstedt G, Lundberg P-A & Bengtsson B-Å 1994 Serum insulin-like growth factor I in a random population sample of men and women: relation to age, sex, smoking habits, coffee consumption and physical activity, blood pressure and concentrations of plasma lipids, fibrinogen, parathyroid hormone and osteocalcin. Clinical Endocrinology 41 351–357.[Medline]
Lee H, Dunwiddie T & Hoffer B 1980 Electrophysiological interactions of enkephalins with neuronal circuitry in the rat hippocampus. II. Effects of interneuron excitability. Brain Research 184 331–342.[CrossRef][Web of Science][Medline]
Liu J, Grinberg A, Westphal H, Sauer B, Accili D, Karas M & LeRoith D 1998 Insulin-like growth factor-I affects perinatal lethality and postnatal development in a gene dosage-dependent manner: manipulation using the Cre/loxP system in transgenic mice. Molecular Endocrinology 12 1452–1462.
Markowska A, Mooney M & Sonntag W 1998 Insulin-like growth factor-I ameliorates age-related behavioral deficits. Neuroscience 87 559–569.[CrossRef][Web of Science][Medline]
Morris R 1981 Spatial localization does not require the presence of local cues. Learning and Motivation 12 239–260.[CrossRef][Web of Science]
Morris R, Garrud P, Rawlins J & O’Keefe J 1982 Place navigation impaired in rats with hippocampal lesions. Nature 297 681–683.[CrossRef][Medline]
Niikura T, Hashimoto Y, Okamoto T, Abe Y, Yasukawa T, Kawasumi M, Hiraki T, Kita Y, Terashita K, Kouyama K et al. 2001 Insulin-like growth factor I (IGF-I) protects cells from apoptosis by Alzheimer’s V6421 mutant amyloid precursor protein through IGF-I receptor in an IGF-binding protein-sensitive manner. Journal of Neuroscience 21 1902–1910.
Nilsson L, Sara V & Nordberg A 1988 Insulin-like growth factor I stimulates the release of acetylcholine from rat cortical slices. Neuroscience Letters 88 221–226.[CrossRef][Web of Science][Medline]
O’Hooge R & De Deyn P 2001 Applications of the Morris water maze in the study of learning and memory. Brain Research. Brain Research Reviews 36 60–90.[CrossRef][Medline]
O’Kusky J, Ye P & D’Ercole A 2000 Insulin-like growth factor-I promotes neurogenesis and synaptogenesis in the hippocampal dentate gyrus during postnatal development. Journal of Neuroscience 20 8435–8442.
Palmiter R, Cole T, Quaife C & Findley S 1996 ZnT-3, a putative transporter of zinc into synaptic vesicles. PNAS 93 14934–14939.
Reinhardt R & Bondy C 1994 Insulin-like growth factors cross the blood–brain barrier. Endocrinology 135 1753–1761.[Abstract]
Saito T, Takahashi K, Nakagawa N, Hosokawa T, Kurasaki M, Yamanoshita O, Yamamoto Y, Sasaki H, Nagashima K & Fujita H 2000 Deficiencies of hippocampal Zn and ZnT3 accelerate brain aging of rat. Biochemical and Biophysical Research Communications 279 505–511.[CrossRef][Web of Science][Medline]
Schultzberg M, Hökfelt T, Terenius L, Elfvin, L Lundberg J, Brandt J, Elde R & Goldstein M 1979. Enkephalin immunoreactive nerve fibres and cell bodies in sympathetic ganglia of the guinea-pig and rat. Neuroscience 4 249–270.[CrossRef][Web of Science][Medline]
Segal M 1977 Morphine and enkephalin interactions with putative neurotransmittors in rat hippocampus. Neuropharmacology 16 587–592.[CrossRef][Web of Science][Medline]
Selkoe D 2002 Alzheimer’s disease is a synaptic failure. Science 298 789–791.
Shigemoto R, Kulik A, Roberts J, Ohishi H, Nusser Z, Kaneko T & Somogyi P 1996 Target-cell-specific concentration of a metabotropic glutamate receptor in the presynaptic active zone. Nature 381 523–525.[CrossRef][Medline]
Sjögren K, Liu J, Blad K, Skrtic S, Vidal O, Wallenius V, LeRoith D, Törnell J, Isaksson OG, Jansson JO et al. 1999 Liver-derived insulin-like growth factor I (IGF-I) is the principle source of IGF-I in blood but is not required for postnatal body growth in mice. PNAS 96 7088–7092.
Sjögren K, Wallenius K, Liu J, Bohlooly YM, Pacini G, Svensson L, Törnell J, Isaksson OG, Ahren B, Jansson JO et al. 2001 Liver-derived IGF-I is of importance for normal carbohydrate and lipid metabolism. Diabetes 50 1539–1545.
Sjögren K, Sheng M, Moverare S, Liu J, Wallenius K, Törnell J, Isaksson OG, Jansson JO, Mohan S & Ohlsson C 2002 Effects of liver-derived insulin-like growth factor I on bone metabolism in mice. Journal of Bone and Mineral Research 17 1977–1987.[CrossRef][Web of Science][Medline]
Sonntag W, Lynch C, Thornton P, Khan A, Bennett S & Ingram R 2000 The effects of growth hormone and IGF-I deficiency on cerebrovascular and brain ageing. Journal of Anatomy 197 575–585.
Sonntag W, Carter C, Ikeno Y, Ekenstedt K, Carlson C, Loeser R, Chakrabarty S, Lee S, Bennett C, Ingram R et al. 2005 Adult-onset growth hormone and insulin-like growth factor I deficiency reduces neoplastic disease, modifies age-related pathology, and increases life span. Endocrinology 146 2920–2932.
Sundström E, Archer T, Melander T & Hökfelt T 1988 Galanin impairs acquisition but not retrieval of spatial memory in rats studied in the Morris swim maze. Neuroscience Letters 88 331–335.[CrossRef][Web of Science][Medline]
Tivesten Å, Bollano E, Andersson I, Fitzgerald S, Caidahl K, Sjögren K, Skott O, Liu J, Mobini R, Isaksson OG et al. 2002 Liver-derived insulin-like growth factor-I is involved in the regulation of blood pressure in mice. Endocrinology 143 4235–4242.
Trejo J, Carro E & Torres-Aleman I 2001 Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. Journal of Neuroscience 21 1628–1634.
Trejo J, Carro E, Lopez-Lopez C & Torres-Aleman I 2004 Role of serum insulin-like growth factor I in mammalian brain aging. Growth Hormone and IGF Research 14 (Suppl A) S39–S43.[CrossRef]
Unger J 1998 Glial reaction in aging and Alzheimer’s disease. Microscopy Research and Technique 43 24–28.[CrossRef][Web of Science][Medline]
van Dam P, de Winter C, de Vries R, van der Grond J, Drent M, Lijffijt M, Kenemans J, Aleman A, de Haan E & Koppeschaar H 2005 Childhood-onset growth hormone deficiency, cognitive function and brain N-acetylaspartate. Psychoneuroendocrinology 30 357–363.[CrossRef][Web of Science][Medline]
Verhofstad A, Steinbusch H, Joosten H, Penke B, Varga J & Goldstein M 1983 Immunocytochemical localization of noradrenaline, adrenaline and serotonin. In Immunocytochemistry: Practical Applications in Pathology and Biology, pp 143–168. Eds JM Polak & S Van Norden. Bristol: Wright.
Vicario-Abejon C, Yusta-Boyo M, Fernandez-Moreno C & de Pablo F 2003 Locally born olfactory bulb stem cells proliferate in response to insulin-related factors and require endogenous insulin-like growth factor-I for differentiation into neurons and glia. Journal of Neuroscience 23 895–906.
Wagner J, Terman G & Chavkin C 1993 Endogenous dynorphins inhibit excitatory neurotransmission and block LTP induction in the hippocampus. Nature 363 451–454.[CrossRef][Medline]
Wallenius K, Sjögren K, Peng X, Park S, Wallenius V, Liu J, Umaerus M, Wennbo H, Isaksson OG, Frohman L et al. 2001 Liver-derived IGF-I regulates GH secretion at the pituitary level in mice. Endocrinology 142 4762–4770.
Weber E, Evans C & Barchas J 1982a Predominance of the amino-terminal octapeptide fragment of dynorphin in rat brain regions. Nature 299 77–79.[CrossRef][Medline]
Weber E, Roth K & Barchas J 1982b Immunohistochemical distribution of alpha-neo-endorphin/dynorphin neuronal systems in rat brain: evidence for colocalization. PNAS 79 3062–3066.
Weisskopf M, Zalutsky R & Nicoll R 1993 The opiod peptide dynorphin mediates heterosynaptic depression of hippocampal mossy fibre synapses and modulates long-term potentiation. Nature 362 423–427.[CrossRef][Medline]
Woods K, Camacho-Hübner C, Savage M & Clark A 1996 Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. New England Journal of Medicine 335 1363–1367.
Yakar S, Liu J, Stannard B, Butler A, Accili D, Sauer B & LeRoith D 1999 Normal growth and development in the absence of hepatic insulin-like growth factor I. PNAS 96 7324–7329.
Received in final form 23 February 2006
Accepted 9 March 2006
Made available online as an Accepted Preprint 13 March 2006
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