Aerobic exercise and a BDNF-mimetic therapy rescue learning and memory in a mouse model of Down syndrome

Martina Parrini,Lucian Medrihan,Laura Cancedda,Diego Ghezzi,Micol Alberti,Andrea Contestabile,Gabriele Deidda,Pietro Baldelli,Enrico Castroflorio

doi:10.1038/s41598-017-17201-8

Abstract

Down syndrome (DS) is caused by the triplication of human chromosome 21 and represents the most frequent genetic cause of intellectual disability. The trisomic Ts65Dn mouse model of DS shows synaptic deficits and reproduces the essential cognitive disabilities of the human syndrome. Aerobic exercise improved various neurophysiological dysfunctions in Ts65Dn mice, including hippocampal synaptic deficits, by promoting synaptogenesis and neurotransmission at glutamatergic terminals. Most importantly, the same intervention also prompted the recovery of hippocampal adult neurogenesis and synaptic plasticity and restored cognitive performance in trisomic mice. Additionally, the expression of brain-derived neurotrophic factor (BDNF) was markedly decreased in the hippocampus of patients with DS. Since the positive effect of exercise was paralleled by increased BDNF expression in trisomic mice, we investigated the effectiveness of a BDNF-mimetic treatment with 7,8-dihydroxyflavone at alleviating intellectual disabilities in the DS model. Pharmacological stimulation of BDNF signaling rescued synaptic plasticity and memory deficits in Ts65Dn mice. Based on our findings, Ts65Dn mice benefit from interventions aimed at promoting brain plasticity, and we provide evidence that BDNF signaling represents a potentially new pharmacological target for treatments aimed at rescuing cognitive disabilities in patients with DS.

Highlights

Neuroprosthetics, Institute of Bioengineering, School of Engineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. 5Present address: Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, NewYork, NY, USA. 6Present address: Laboratory of Neurophysiology, Department of Physiology and Biochemistry, University of Malta, Msida, Malta
Among the many molecular players involved in the positive effect of exercise, brain-derived neurotrophic factor (BDNF) signaling through its tropomyosin-receptor-kinase B (TrkB) receptor is known to play a pivotal role in both enhanced brain plasticity and cognition[47,49,50,51,52]
We aimed to investigate the effects of strategies that stimulate brain neuroplasticity mechanisms on the rescue of learning and memory deficits observed in the Ts65Dn mouse model of Down syndrome (DS)

Summary

Introduction

The beneficial effects of aerobic exercise have been associated with the upregulation of BDNF expression, increased adult neurogenesis in the hippocampal DG and potentiation of synaptic plasticity[23,24,25,29,30,31,32,33,40,41,42,43,44,45,46,47,48]. We report a detailed biochemical, structural, electrophysiological and behavioral assessment of the positive effect of aerobic exercise on the corresponding deficits observed in trisomic animals, indicating that exercise is a valuable tool to promote brain plasticity and possibly represents a complementary therapeutic approach to pharmacologic interventions in patients with DS. We identified a new pharmacological target to treat DS-associated cognitive impairment

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Conclusion