Administration of cyclic glycine-proline during infancy improves adult spatial memory, astrocyte plasticity, vascularization and GluR-1 expression in rats

ABSTRACT

Cyclic glycine-proline (cGP) is a natural nutrient of breast milk and plays a role in regulating the function of insulin-like growth factor-1 (IGF-1). IGF-1 function is essential for post-natal brain development and adult cognitive function. We evaluated the effects of cGP on spatial memory and histological changes in the hippocampus of the adult rats following infancy administration. Infant rats were treated with either cGP or saline between post-natal days 8 and 22 via oral administration to lactating dams. The spatial memory was evaluated between post-natal days 70 and 75 using Morris water maze tests. The changes of capillaries, astrocytes, synaptophysin and glutamate receptor-1 were examined in the CA1 stratum radiatum of the hippocampus. Compared to saline-treated group, cGP-treated group showed higher path efficiency of entry and lower average heading errors to the platform zone. cGP-treated group also showed longer, larger and more astrocytic processes, more capillaries and higher glutamate receptor-1 expression. The rats made less average heading error to the platform zone have more capillaries, larger and longer astrocytic branches. Thus cGP treatment/supplementation during infancy moderately improved adulthood spatial memory. This long-lasting effect of cGP on memory could be mediated via promoting astrocytic plasticity, vascularization and glutamate trafficking. Therefore, cGP may have a role in regulating IGF-1 function during brain development.

KEYWORDS:

• Cyclic glycine-proline
• insulin-like growth factor-1
• Morris water maze tests
• spatial reference memory
• astrocytic plasticity
• glutamate receptor-1
• cerebral vascular densities
• post-natal brain development

Acknowledgements

This work was supported by Gravida, National Centre for Growth and Development, Liggins Institute, University of Auckland, New Zealand (Grant number: 3709177), the Ministry of Business, Innovation and Employment (MBIE), Wellington, New Zealand (Grant number: FRST C10X0702). The Swedish Research Council (VR:201701409) and the Swedish Brain Foundation (FO:2019-0270).

Authors contributions

G. S. M. conducted the animal experiments, performed the immunohistochemical staining, analyzed the data, and wrote the manuscript. M. A. performed morphological quantification and statistical analysis and assisted in manuscript preparation. K. S. and C.D.M. provided funding for experimental tests and helped in sample collection and manuscript revisions. C. M. provided funding for histological analysis of the tissue and helped in manuscript revisions. J. G. designed the experiment, provided funding for research, helped in sample collection, and co-wrote and revised the manuscript.

Data availability

All data generated or analyzed during this study are included in this article. Additional datasets analyzed during the current study are available from the corresponding author on reasonable request.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by Ministry of Business, Innovation and Employment: [Grant Number FRST C10X0702]; Swedish Brain foundation [grant number FO:2019-0270]; The Swedish Research Council [grant number VR:201701409]; Tertiary Education Commission [grant number 3709177].

Notes on contributors

Gagandeep Singh-Mallah

Gagandeep Singh-Mallah is currently an employee of AstraZeneca;

Jian Guan

Jian Guan is also an employee of The cGP Lab Limited, New Zealand, a private company developing cGP-rich natural products for supporting health.