Growth hormone modulates hippocampal excitatory synaptic transmission and plasticity in old rats

Department of Neurobiology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Neurobiology of aging (Impact Factor: 5.01). 10/2011; 33(9):1938-49. DOI: 10.1016/j.neurobiolaging.2011.09.014
Source: PubMed


Alterations in the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPA-R) and N-methyl-D-aspartate receptor (NMDA-R) have been documented in aged animals and may contribute to changes in hippocampal-dependent memory. Growth hormone (GH) regulates AMPA-R and NMDA-R-dependent excitatory transmission and decreases with age. Chronic GH treatment mitigates age-related cognitive decline. An in vitro CA1 hippocampal slice preparation was used to compare hippocampal excitatory transmission and plasticity in old animals treated for 6-8 months with either saline or GH. Our findings indicate that GH treatment restores NMDA-R-dependent basal synaptic transmission in old rats to young adult levels and enhances both AMPA-R-dependent basal synaptic transmission and long-term potentiation. These alterations in synaptic function occurred in the absence of changes in presynaptic function, as measured by paired-pulse ratios, the total protein levels of AMPA-R and NMDA-R subunits or in plasma or hippocampal levels of insulin-like growth factor-I. These data suggest a direct role for GH in altering age-related changes in excitatory transmission and provide a possible cellular mechanism through which GH changes the course of cognitive decline.

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    • "Within the hippocampus, application of exogenous GH is sufficient to induce synaptic plasticity (Zearfoss et al., 2008). Exogenous GH also facilitates hippocampal synaptic transmission (Mahmoud and Grover, 2006; Molina et al., 2012) and hippocampus-dependent eyeblink conditioning is associated with enhanced GH protein synthesis in hippocampal cells (Donahue et al., 2002). Interestingly, hippocampal GH levels are stress-sensitive: GH gene transcription is regulated by glucocorticoid stress hormones (Treacy et al., 1991) and GH protein levels are increased one day after an acute stress exposure (Donahue et al., 2006). "
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    ABSTRACT: Though growth hormone (GH) is synthesized by hippocampal neurons, where its expression is influenced by stress exposure, its function is poorly characterized. Here, we show that a regimen of chronic stress that impairs hippocampal function in rats also leads to a profound decrease in hippocampal GH levels. Restoration of hippocampal GH in the dorsal hippocampus via viral-mediated gene transfer completely reversed stress-related impairment of two hippocampus-dependent behavioral tasks, auditory trace fear conditioning, and contextual fear conditioning, without affecting hippocampal function in unstressed control rats. GH overexpression reversed stress-induced decrements in both fear acquisition and long-term fear memory. These results suggest that loss of hippocampal GH contributes to hippocampal dysfunction following prolonged stress and demonstrate that restoring hippocampal GH levels following stress can promote stress resilience.
    Frontiers in Behavioral Neuroscience 06/2013; 7:66. DOI:10.3389/fnbeh.2013.00066 · 3.27 Impact Factor
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    • "Several memory impairments in old rats may be partially due to abnormal glutamate function, and it was suggested that GH can mitigate the age-related changes in hippocampal function that underlie this cognitive impairment. In this context Molina et al. (2012) reported that old animals treated for 6–8 months with GH restored NMDAreceptor-dependent basal synaptic transmission to young adult levels and enhanced both AMPA-receptor-dependent basal synaptic transmission and long-term potentiation. Table 1 Object recognition index. "
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    ABSTRACT: It has been reported that Growth hormone (GH) has an immediate effect enhancing excitatory postsynaptic potentials mediated by AMPA and NMDA receptors in hippocampal area CA1. As GH plays a role in adult memory processing, this work aims to study the acute effects of GH on working memory tasks in rodents and the possible involvement of NMDA and AMPA receptors and also the MEK/ERK signalling pathway. To evaluate memory processes, two different tests were used, the spatial working memory 8-arm radial maze, and the novel object recognition as a form of non-spatial working memory test. Acute GH treatment (1 mg/kg i.p., 1h) improved spatial learning in the radial maze respect to the control group either in young rats (reduction of 46% in the performance trial time and 61% in the number of errors), old rats (reduction of 38% in trial time and 48% in the number of errors), and adult mice (reduction of 32% in the performance time and 34% in the number of errors). GH treatment also increased the time spent exploring the novel object respect to the familiar object compared to the control group in young rats (from 63% to 79%), old rats (from 53% to 70%), and adult mice (from 61 to 68%). The improving effects of GH on working memory tests were blocked by the NMDA antagonist MK801 dizocilpine (0.025 mg/kg i.p.) injected 10 min before the administration of GH, in both young and old rats. In addition, the AMPA antagonist DNQX (1 mg/kg i.p.) injected 10 min before the administration of GH to young rats, blocked the positive effect of GH. Moreover, in mice, the MEK inhibitor SL 327 (20 mg/kg i.p.) injected 30 min before the administration of GH, blocked the positive effect of GH on radial maze and the novel object recognition. In conclusion, GH improved working memory processes through both glutamatergic receptors NMDA and AMPA and it required the activation of extracellular MEK/ERK signalling pathway. These effects could be related to the enhancement of excitatory synaptic transmission in the hippocampus reported by GH.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 04/2013; 45. DOI:10.1016/j.pnpbp.2013.04.005 · 3.69 Impact Factor
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    ABSTRACT: In rats, as in humans, normal aging is characterized by a decline in hippocampal-dependent learning and memory, as well as in glutamatergic function. Both growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels have been reported to decrease with age, and treatment with either GH or IGF-I can ameliorate age-related cognitive decline. Interestingly, acute GH and IGF-I treatments enhance glutamatergic synaptic transmission in the rat hippocampus of juvenile animals. However, whether this enhancement also occurs in old rats, when cognitive impairment is ameliorated by GH and IGF-I (des-IGF-I), remains to be determined. To address this issue, we used an in vitro CA1 hippocampal slice preparation and extracellular recording techniques to study the effects of acute application of GH and IGF-I on compound field excitatory postsynaptic potentials (fEPSPs), as well as AMPA- and NMDA-dependent fEPSPs, in young adult (10 months) and old (28 months) rats. The results indicated that both GH and IGF-I increased compound-, AMPA-, and NMDA-dependent fEPSPs to a similar extent in slices from both age groups and that this augmentation was likely mediated via a postsynaptic mechanism. Initial characterization of the signaling cascades underlying these effects revealed that the GH-induced enhancement was not mediated by the JAK2 signaling element in either young adult or old rats but that the IGF-I-induced enhancement involved a PI3K-mediated mechanism in old, but not young adults. The present findings are consistent with a role for a GH- or IGF-I-induced enhancement of glutamatergic transmission in mitigating age-related cognitive impairment in old rats.
    Age 08/2012; 35(5). DOI:10.1007/s11357-012-9460-4 · 3.45 Impact Factor
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