Maternal Zinc Diet Impairs Learning and Memory in Offspring Rats through the CREB/BDNF Pathway
Abstract
BACKGROUND: Zinc released into the synaptic cleft able to modulate various signaling pathways, including brain derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase B (TrkB). Zinc binding to its receptor, G-protein coupled receptor 39 (GPR39), may trigger biochemical pathways leading to cAMP response element binding protein (CREB)-dependent gene transcription that subsequently promotes BDNF upregulation. Therefore, zinc dyshomeostasis should be considered as a condition that induces disruption of CREB/BDNF signaling. This study was conducted to examine the effect of maternal zinc diet on hippocampal expression levels of CREB and BDNF in offspring.
METHODS: One-day pregnant rats were randomly divided into five groups: zinc-deficient (D), zinc-restricted (R), zinc-adequate (A), zinc-supplemented (S), and excess zinc-supplemented (ES). The groups had different zinc diets during pregnancy and lactation. The behavioral function of the offspring was tested with Y-maze at the 43th postnatal. Hippocampus was isolated, BDNF was assessed by quantitative real-time polymerase chain reaction (qRT-PCR), and CREB was examined using sandwich enzyme-linked immunosorbent assay (ELISA).
RESULTS: Spatial working memory measurement demonstrated that D and ES group exhibited a significantly lower spontaneous alternation than other groups. The qRT-PCR and ELISA analysis revealed the hippocampal expression level of BDNF and CREB decreased in groups D and ES, but tended to increase in groups R and S, until the highest expression peak was found in group A.
CONCLUSION: High and low intake of zinc induces lower expression of BDNF and CREB in hippocampus, which further impairs learning and memory. Our findings suggest the signaling pathway of CREB/BDNF is involved in zinc dyshomeostasis-induced cognitive impairments.
KEYWORDS: hippocampus, BDNF, CREB, TrkB, GPR39, zinc, diet, LTP
Full Text:
PDFReferences
Narváez-Caicedo C, Moreano G, Sandoval BA, Jara-Palacios MÁ. Zinc deficiency among lactating mothers from a Peri-Urban Community of the Ecuadorian Andean Region: an initial approach to the need of zinc supplementation. Nutrients. 2018; 10(7): 869, CrossRef.
Caulfield LE, Black RE. Zinc deficiency. In: Ezzati M, Lopez AD, Rodgers A, Murray CJL, editors. Comparative Quantification of Health Risks: Global and Regional Burden of Diseases Attributable to Selected Major Risks. Geneva: World Health Organization; 2004. p.257-79, article.
Fernandes FS, de Souza AS, do Carmo M, Boaventura GT. Maternal intake of flaxseed-based diet (Linum usitatissimum) on hippocampus fatty acid profile: implications for growth, locomotor activity and spatial memory. Nutrition. 2011; 27(10): 1040-7, CrossRef.
Shah D, Sachdev HP. Zinc deficiency in pregnancy and fetal outcome. Nutr Rev. 2006; 64(1): 15-30, CrossRef.
Gao HL, Zheng W, Xin N, Chi ZH, Wang ZY, Chen J, et al. Zinc deficiency reduces neurogenesis accompanied by neuronal apoptosis through caspase-dependent and -independent signaling pathways. Neurotox Res. 2009; 16(4): 416-25, CrossRef.
Guidolin D, Polato P, Venturin G, Zanotti A, Mocchegiani E, et al. Correlation between zinc level in hippocampal mossy fibers and spatial memory in aged rats. Ann NY Acad Sci. 1992; 673: 187-93, CrossRef.
Yu SM, Kogan MD, Gergen P. Vitamin-mineral supplement use among preschool children in the United States. Pediatrics. 1997; 100(5): E4, CrossRef.
Brown KH, Peerson JM, Baker SK, Hess SY. Preventive zinc supplementation among infants, preschoolers, and older prepubertal children. Food Nutr Bull. 2009; 30(1): 12-40, CrossRef.
Kusumastuti AC, Ardiaria M, Hendrianingtyas M. Effect of zinc and iron supplementation on appetite, nutritional status, and intelligence quotient in young children. Indones Biomed J. 2018; 10(2): 133-9, CrossRef.
Huybrechts I, Maes L, Vereecken C, De Keyzer W, De Bacquer D, et al. High dietary supplement intakes among Flemish preschoolers. Appetite. 2010; 54(2): 340-5, CrossRef.
Malik R, Chattarji S. Enhanced intrinsic excitability and EPSP-spike coupling accompany enriched environment-induced facilitation of LTP in hippocampal CA1 pyramidal neurons. J Neurophysiol. 2012; 107(5): 1366-78, CrossRef.
Bramham CR, Messaoudi E. BDNF function in adult synaptic plasticity: The synaptic consolidation hypothesis. Prog Neurobiol. 2005; 76(2): 99-125, CrossRef.
Hwang JJ, Park MH, Choi SY, Koh JY. Activation of the Trk signaling pathway by extracellular zinc: Role of metalloproteinases. J Biol Chem. 2005; 280(12): 11995-2001, CrossRef.
Yoo MH, Kim TY, Yoon YH and Koh JY. Autism phenotypes in ZnT3 null mice: involvement of zinc dyshomeostasis, MMP-9 activation and BDNF upregulation. Nat Sci Rep. 2016; 6: 28548, CrossRef.
Cunha C, Brambilla R, Thomas KL. A simple role for BDNF in learning and memory? Front Mol Neurosci. 2010; 3: 1, CrossRef.
Sowa-Kucma M, Legutko B, Szewczyk B, Novak K, Znojek P, Poleszak E, et al. Antidepressant-like activity of zinc: further behavioral and molecular evidence. J Neural Transm. 2008; 115; 1621-28, CrossRef.
Chowanadisai W, Kelleher SL, Lonnerdal B. Maternal zinc deficiency reduces NMDA receptor expression in neonatal rat brain, which persists into early adulthood. J Neurochem. 2005; 94: 510-9, CrossRef.
Yu X, Ren T, Yu X. Disruption of calmodulin-dependent protein kinase II α/brain-derived neurotrophic factor (α-CaMKII/BDNF) signalling is associated with zinc deficiency-induced impairments in cognitive and synaptic plasticity. Br J Nutr. 2013; 110(12): 2194-200, CrossRef.
Yang Y, Jing XP, Zhang SP, Gu RX, Tang FX, et al. High dose zinc supplementation induces hippocampal zinc deficiency and memory impairment with inhibition of BDNF signaling. PLoS ONE. 2013; 8(1): e55384, CrossRef.
Yu X, Jin L, Zhang X, Yu X. Effects of maternal mild zinc deficiency and zinc supplementation in offspring on spatial memory and hippocampal neuronal ultrastructural changes. Nutrition. 2013; 29(2): 457-61, CrossRef.
Jiang YG, Fang HY, Pang W, Liu J, Lu H, Ma Q, Fang HT. Depressed hippocampal MEK/ERK phosphorylation correlates with impaired cognitive and synaptic function in zinc-deficient rats. Nutr Neurosci. 2011; 14(2): 45-50, CrossRef.
Gao HL, Xu H, Xin N, Zheng W, Chi ZH, Wang ZY. Disruption of the CaMKII/CREB signaling is associated with zinc deficiency-induced learning and memory impairments. Neurotox Res. 2011; 19(4): 584-91, CrossRef.
Yoshida K, Gi M, Fujioka M, Teramoto I, Wanibuchi H. Long-term administration of excess zinc impairs learning and memory in aged mice. J Toxicol Sci. 2019; 44(10): 681-91, CrossRef.
Sindreu C, Palmiter RD, Storm DR. Zinc transporter ZnT-3 regulates presynaptic Erk1/2 signaling and hippocampus-dependent memory. Proc Natl Acad Sci USA. 2011; 108(8): 3366-70, CrossRef.
Hamadani JD, Fuchs GJ, Osendarp SJ, Huda SN, Grantham-McGregor SM. Zinc supplementation during pregnancy and effects on mental development and behaviour of infants: a follow-up study. Lancet. 2002; 360(9329): 290-4, CrossRef.
Doboszewska U, Szewczyk B, Sowa-Kućma M, Młyniec K, Nowak G. The disruption of CREB/BDNF/TrkB signaling. Dynamic changes induced by zinc deficiency. Pharmacol Rep. 2013; 65 (Suppl 1): 119-20, CrossRef.
Tropea TF, Kosofsky BE, Rajadhyaksha AM. Enhanced CREB and DARPP-32 phosphorylation in the nucleus accumbens and CREB, ERK, and GluR1 phosphorylation in the dorsal hippocampus is associated with cocaine-conditioned place preference behavior. J Neurochem. 2008; 106(4): 1780-90, CrossRef.
Saura CA, Valero J. The role of CREB signaling in Alzheimer's disease and other cognitive disorders. Rev Neurosci. 2011; 22(2): 153-69, CrossRef.
Kasarpalkar NJ, Kothari ST, Dave UP. Brain-derived neurotrophic factor in children with autism spectrum disorder. Ann Neurosci. 2014; 21(4): 129-33, CrossRef.
Russo AJ, Mensah A, Bowman J. Decreased phosphorylated CREB and AKT in individuals with autism normalized after zinc therapy. Acad J Ped Neonatol. 2017; 5(3): 57-60, CrossRef.
Li Y, Hough CJ, Suh SW, Sarvey JM, Frederickson CJ. Rapid translocation of Zn(2+) from presynaptic terminals into postsynaptic hippocampal neurons after physiological stimulation. J Neurophysiol. 2001; 86(5): 2597-604, CrossRef.
Noh KM, Koh JY. Induction and activation by zinc of NADPH oxidase in cultured cortical neurons and astrocytes. J Neurosci. 2000; 20(23): RC111, CrossRef.
Chen F, Yu Y, Haigh S, Johnson J, Lucas R, Stepp DW, Fulton DJ. Regulation of NADPH oxidase 5 by protein kinase C isoforms. PLoS One. 2014; 9(2): e88405, CrossRef.
Marreiro DD, Cruz KJ, Morais JB, Beserra JB, Severo JS, de Oliveira AR. Zinc and oxidative stress: Current mechanisms. Antioxidants. 2017; 6(2): 24, CrossRef.
Cichy A, Sowa-Kućma M, Legutko B, Pomierny-Chamioło L, Siwek A, Piotrowska A, et al. Zinc-induced adaptive changes in NMDA/glutamatergic and serotonergic receptors. Pharmacol Rep. 2009; 61(6): 1184-91, CrossRef.
Cieślik K, Sowa-Kućma M, Ossowska G, Legutko B, Wolak M, Opoka W, et al. Chronic unpredictable stress-induced reduction in the hippocampal brain-derived neurotrophic factor (BDNF) gene expression is antagonized by zinc treatment. Pharmacol Rep. 2011; 63(2): 537-43, CrossRef.
Sowa-Kućma M, Legutko B, Szewczyk B, Novak K, Znojek P, Poleszak E, et al. Antidepressant-like activity of zinc: further behavioral and molecular evidence. J Neural Transm. 2008; 115(12): 1621-8, CrossRef.
Mlyniec K. Zinc in the glutamatergic theory of depression. Curr Neuropharmacol. 2015; 13(4): 505-13, CrossRef.
Nowak G, Szewczyk B. Mechanisms contributing to antidepressant zinc actions. Pol J Pharmacol. 2002; 54(6): 587-92, PMID.
Hwang JJ, Park MH, Choi SY, Koh JY. Activation of the Trk signaling pathway by extracellular zinc. Role of metalloproteinases. J Biol Chem. 2005; 280(12): 11995-2001, CrossRef.
DOI: https://doi.org/10.18585/inabj.v16i3.3021
Copyright (c) 2024 The Prodia Education and Research Institute
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Indexed by:
The Prodia Education and Research Institute
