Elsevier

Neuroscience

Volume 113, Issue 3, 2 September 2002, Pages 607-615
Neuroscience

Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents

https://doi.org/10.1016/S0306-4522(02)00162-8Get rights and content

Abstract

Leptin is well known to be involved in the control of feeding, reproduction and neuroendocrine functions through its action on the hypothalamus. However, leptin receptors are found in brain regions other than the hypothalamus (including the hippocampus and cerebral cortex) suggesting extrahypothalamic functions. We investigated hippocampal long-term potentiation (LTP) and long-term depression (LTD), and the spatial-memory function in two leptin receptor-deficient rodents (Zucker rats and db/db mice). In brain slices, the CA1 hippocampal region of both strains showed impairments of LTP and LTD; leptin (10−12 M) did not improve these impairments in either strain. These strains also showed lower basal levels of Ca2+/calmodulin-dependent protein kinase II activity in the CA1 region than the respective controls, and the levels did not respond to tetanic stimulation. These strains also showed impaired spatial memory in the Morris water-maze test (i.e. longer swim-path lengths during training sessions and less frequent crossings of the platform’s original location in the probe test.

From these results we suggest that the leptin receptor-deficient animals show impaired LTP in CA1 and poor spatial memory due, at least in part, to a deficiency in leptin receptors in the hippocampus.

Section snippets

Animals

Male db/db mice (C57BL/KsJ-db/db Jc1) and Zucker fatty rats (fa/fa) (all 7 weeks old) and their respective controls (C57BL/KsJ-db/+m Jc1 and +/+) were fed commercial food pellets (Clea Japan, Japan) and allowed free access to tap water. They were maintained in a colony room with an ambient temperature of 24±1°C and a 07.00/19.00 h light/dark photocycle. All procedures were approved by the Animal Care and Use Committee of Kyushu University and conformed to the guidelines for the use of

LTP, LTD and post-synaptic responses of CA1 neurons in Zucker rats

Fig. 1 illustrates the results obtained in Zucker fatty rats: it shows the evoked pEPSPs before and after tetanic stimulation in normal Krebs–Ringer solution and in a solution containing 10−12 M leptin. A brief PTP was seen in each solution, but LTP did not appear with or without leptin. However, as shown in Fig. 2, in control Zucker lean rats, this concentration of leptin enhanced the LTP maintenance by approximately twice (compared with that seen in normal Krebs–Ringer solution), while 10−10

Discussion

The present study demonstrated that Zucker fatty rats and db/db mice, both of which are deficient in OB-Rs, showed impairments of LTP and LTD in the CA1 hippocampal region. Although leptin enhanced LTP maintenance at 10−12 M and inhibited it at 10−10 M in lean control rats, Zucker fatty rats and db/db mice were both insensitive to leptin.

In the Morris water-maze test, Zucker rats and db/db mice each swam further than their controls before they found and climbed onto the platform under

Conclusion

In the present study, we demonstrated that Zucker fatty rats and db/db mice both showed impairments in LTP and LTD in hippocampal CA1 neurons, as well as deficits in spatial memory. This may be, at least in part, secondary to the deficiency of OB-Rs in these two animal trains. On the basis of these results, we propose that in addition to its previously reported roles, leptin may have an important role to play in the regulation of hippocampal functions and in the control of learning and memory

Acknowledgements

We thank Dr. R. Timms for a critical reading of the manuscript. This work was supported by Grants-in-Aid for Scientific Research 10470011 (to S.A.) and 11877014 (to S.A.) from the Ministry of Education, Science, and Culture of Japan.

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