Elsevier

Peptides

Volume 27, Issue 11, November 2006, Pages 2738-2749
Peptides

Leptin facilitates learning and memory performance and enhances hippocampal CA1 long-term potentiation and CaMK II phosphorylation in rats

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Abstract

Leptin, an adipocytokine encoded by an obesity gene and expressed in adipose tissue, affects feeding behavior, thermogenesis, and neuroendocrine status via leptin receptors distributed in the brain, especially in the hypothalamus. Leptin may also modulate the synaptic plasticity and behavioral performance related to learning and memory since: leptin receptors are found in the hippocampus, and both leptin and its receptor share structural and functional similarities with the interleukin-6 family of cytokines that modulate long-term potentiation (LTP) in the hippocampus. We therefore examined the effect of leptin on (1) behavioral performance in emotional and spatial learning tasks, (2) LTP at Schaffer collateral-CA1 synapses, (3) presynaptic and postsynaptic activities in hippocampal CA1 neurons, (4) the intracellular Ca2+ concentration ([Ca2+]i) in CA1 neurons, and (5) the activity of Ca2+/calmodulin protein kinase II (CaMK II) in the hippocampal CA1 tissue that exhibits LTP. Intravenous injection of 5 and/or 50 μg/kg, but not of 500 μg/kg leptin, facilitated behavioral performance in passive avoidance and Morris water-maze tasks. Bath application of 10−12 M leptin in slice experiments enhanced LTP and increased the presynaptic transmitter release, whereas 10−10 M leptin suppressed LTP and reduced the postsynaptic receptor sensitivity to N-methyl-d-aspartic acid. The increase in the [Ca2+]i induced by 10−10 M leptin was two times greater than that induced by 10−12 M leptin. In addition, the facilitation (10−12 M) and suppression (10−10 M) of LTP by leptin was closely associated with an increase and decrease in Ca2+-independent activity of CaMK II. Our results show that leptin not only affects hypothalamic functions (such as feeding, thermogenesis, and neuroendocrine status), but also modulates higher nervous functions, such as the behavioral performance related to learning and memory and hippocampal synaptic plasticity.

Introduction

Activity-dependent synaptic plasticity is widely accepted as part of the neurophysiological basis of learning and memory [6], [62]. Long-term potentiation (LTP), which has been mainly studied in the CA1 region of the hippocampus, is one form of activity-dependent synaptic plasticity [5], [36], [37]. Brief high-frequency afferent stimulation produces LTP in which a long-lasting increase in the strength of synaptic transmission occurs. It is known that LTP is triggered by a postsynaptic increase in the intracellular Ca2+ concentration ([Ca2+]i). Following such a rise in [Ca2+]i, the production of LTP requires the activation of a Ca2+-sensitive protein kinase such as Ca2+/calmodulin-dependent protein kinase II (CaMK II) [5], [16], [36].

Leptin, an adipocytokine encoded by an obesity gene and expressed in adipose tissue, is increased in rat plasma during eating, the rise being from approximately 2.3 to 3.8 ng/ml (i.e. to 2.4 × 10−10 M) [3]. Leptin binds to widely distributed long-form leptin receptors (OBRb) in the brain, especially in the hypothalamus [22], [56], modulates neuronal activity [46], [57], [58], and affects feeding behavior, thermogenesis, and neuroendocrine status. For example, the lack of leptin seen in ob/ob mice is associated with obesity, hypothermia, and corticosterone elevation, and administering leptin to these mice corrects these abnormalities [10], [24], [41].

Recently, it has been demonstrated that cytokines are important in the modulation of synaptic plasticity [27]. In fact, brain-derived neurotrophic factor enhances LTP in the hippocampus [15], and acidic and basic fibroblast growth factors have been shown to promote the induction of LTP in the CA1 region [53], [66]. In contrast, interleukin-2 and interleukin-6 inhibit LTP [29], [64], [65]. Interestingly, both leptin and its receptor share structural and functional similarities with the interleukin-6 family of cytokines [13]. Moreover, OBRb has been found to be expressed in the CA1 region of the hippocampus [22], [56]. These findings suggest that leptin may affect the synaptic plasticity and behavioral performance related to learning and memory. Indeed, it has been reported that the hippocampal synaptic plasticity is modulated by leptin in rats with intact leptin receptors [12], [55], [72], whereas it is impaired in leptin receptor deficient rodents [19], [31]. However, the effect of leptin on behavioral performance related to learning and memory is unclear. In addition, a relation between leptin and hippocampal synaptic plasticity remains to be elucidated.

In the present study, we examine the effects of leptin on (1) behavioral performance in emotional and spatial learning tasks, (2) LTP at Schaffer collateral-CA1 synapses, (3) presynaptic and postsynaptic activities in hippocampal CA1 neurons, (4) [Ca2+]i in CA1 neurons, and (5) CaMK II activity in the hippocampal CA1 tissue that exhibits LTP, and show that the low dose of leptin enhances behavioral performance and LTP, whereas the high dose of leptin impairs them.

Section snippets

Animals

All animals were male Wistar rats from Charles River Japan, if not otherwise stated. They were housed in an air- and light-controlled room at a temperature of 23 ± 1 °C, lights being on from 7:00 to 19:00. Food and water were available ad libitum. The animals and procedures used were approved by the Animal Care and Use Committees of the Tokyo Medical, Kyushu, Toyama and Tokai Universities and the Jichi Medical School.

Passive avoidance task

Rats aged 6–7 weeks at the beginning of the experiments were used. The

Leptin enhances learning and memory in passive shock-avoidance

The effects of leptin on learning in the passive shock-avoidance test (carried out on four consecutive days) are presented in Fig. 1. Long latencies indicate better performance. On day 1, all groups performed similarly, all displaying short latencies. On days 2–4, retention latency increased day by day in all five groups. The performance of the animals in the 0.5 and 500 μg/kg leptin groups was not significantly better than the control (vehicle) group on days 2 through 4. On days 2 and 3, a

Discussion

In the present in vivo experiments, retention of passive shock-avoidance was enhanced with 5 and 50 μg/kg leptin, but not with 0.5 and 500 μg/kg leptin. Spatial learning and memory performance was unchanged with 0.5 and 5 μg/kg leptin, enhanced with 50 μg/kg leptin, and impaired with 500 μg/kg. In the in vitro experiments, 10−14 M leptin was relatively ineffective on LTP, 10−12 M enhanced LTP, and 10−10 M suppressed it. Thus, the present behavioral and LTP experiments demonstrate that leptin shows an

Conclusions

The results we obtained with a low dose of leptin demonstrate how a physiological increase in plasma leptin (for example, produced by a meal), could prime hippocampal synapses for an enhancement of LTP, and thereby facilitate learning and memory formation. Eating not only maintains the body's energy homeostasis, but may also prime the brain to facilitate learning and memory. This would be a positive advantage to an animal, in making it possible to develop a strategy to both find and remember

Acknowledgments

This work was partly supported by the Japanese Ministry of Education, Culture, Sports, Science and Technology via Grants-in-Aid for Scientific Research (to NH, KS, TY, and TS), and by a Special Coordination Funds for Prompting Science and Technology (to KS). One of the authors (KS) would particularly like to thank Mr. Chikamitsu Nakayama for his encouragement throughout the present work.

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