Abstract
The increase in incidence and prevalence of neurodegenerative diseases highlights the need for a more comprehensive understanding of how food components may affect neural systems. In particular, flavonoids have been recognized as promising agents capable of influencing different aspects of synaptic plasticity resulting in improvements in memory and learning in both animals and humans. Our previous studies highlight the efficacy of flavonoids in reversing memory impairments in aged rats, yet little is known about the effects of these compounds in healthy animals, particularly with respect to the molecular mechanisms by which flavonoids might alter the underlying synaptic modifications responsible for behavioral changes. We demonstrate that a 3-week intervention with two dietary doses of flavonoids (Dose I: 8.7 mg/day and Dose II: 17.4 mg/day) facilitates spatial memory acquisition and consolidation (24 recall) (p < 0.05) in young healthy rats. We show for the first time that these behavioral improvements are linked to increased levels in the polysialylated form of the neural adhesion molecule (PSA-NCAM) in the dentate gyrus (DG) of the hippocampus, which is known to be required for the establishment of durable memories. We observed parallel increases in hippocampal NMDA receptors containing the NR2B subunit for both 8.7 mg/day (p < 0.05) and 17.4 mg/day (p < 0.001) doses, suggesting an enhancement of glutamate signaling following flavonoid intervention. This is further strengthened by the simultaneous modulation of hippocampal ERK/CREB/BDNF signaling and the activation of the Akt/mTOR/Arc pathway, which are crucial in inducing changes in the strength of hippocampal synaptic connections that underlie learning. Collectively, the present data supports a new role for PSA-NCAM and NMDA-NR2B receptor on flavonoid-induced improvements in learning and memory, contributing further to the growing body of evidence suggesting beneficial effects of flavonoids in cognition and brain health.
Highlights
Physical exercise and a diet rich in fruit and vegetables are known to strongly influence the prevalence, and onset of, cardiovascular disease and neurological disorders (Kromhout et al, 2002; Parrott and Greenwood, 2007)
Research into the impact of flavonoid-rich foods on memory, learning and cognitive performance has primarily focused on their potential to reverse cognitive deficits in aged animals (Casadesus et al, 2004; Li et al, 2009a,b) or transgenic mouse models of neurodegenerative disease, such as Alzheimer Disease (Joseph et al, 2003)
We show that a 3-week supplementation with 8.7 mg or 17.4 mg of flavonoids per day (Table 1) is effective in improving spatial learning and memory in healthy, young animals
Summary
Physical exercise and a diet rich in fruit and vegetables are known to strongly influence the prevalence, and onset of, cardiovascular disease and neurological disorders (Kromhout et al, 2002; Parrott and Greenwood, 2007). Rendeiro et al / Neuropharmacology 79 (2014) 335e344 pathways, increased CREB phosphorylation and elevated BDNF levels in the hippocampus Such signaling pathways regulate downstream changes in receptor density and cell adhesion molecule expression/recruitment, crucial events in the regulation of various aspects of synaptic function (Cull-Candy et al, 2001; Muller et al, 2000; Sheng and Kim, 2002). With regards to the former, NMDA receptors (NMDAR) and AMPA receptors (AMPA-R) are key mediators of excitatory synaptic transmission in the hippocampus, and their regulation is regarded as vital for the induction and maintenance of LTP (CullCandy and Leszkiewicz, 2004; Kim et al, 2005; Li and Keifer, 2009). Flavonoid-rich foods, such as blueberry, have previously been shown to regulate receptors involved in hippocampal plasticity, notably IGF-1 and its receptor (Casadesus et al, 2004) and levels of NMDAR subunits (Coultrap et al, 2008)
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