As stroke induces structural plasticity and behavioral adaptation, strategies that promote functional recovery following stroke have gained prospective attention. Brain-derived neurotrophic factor (BDNF) plays a critical role in CNS repair and plasticity. A single nucleotide polymorphism (SNP) of the prodomain of the bdnf gene occurs with high frequency in humans. However, the effect of this SNP on CNS recovery has been controversial. The current proposal addresses this controversy by investigating the extent to which BDNF SNP impacts motor recovery following stroke using mice that contain humanized SNP in both alleles (BDNFMet/Met) or one allele (BDNF+/Met). In spite of greater impairments during the acute phase, BDNFMet/Met mice displayed an unexpected increase in motor/gait function during the stroke recovery phase, especially in the ipsilateral hind limb, and increased striatal volume in the non-injured hemisphere compared to wild type (WT) mice. This was accompanied by increased gene expression of excitatory synaptic markers in this hemisphere. Since activity-regulated BDNF secretion is important for the maturation of inhibitory synapses, and this type of secretion is reduced in BDNFMet/Met neurons, we hypothesize that the BDNFMet allele promotes compensatory motor recovery by reducing the inhibitory synapses leading to synaptic excitation in, and hypertrophy of, the contralateral striatum.
Aim 1 will test the hypothesis that the BDNFMet allele promotes motor recovery via effects in the contralateral striatum. Using WT, BDNF+/Met, and BDNFMet/Met mice subjected to ischemic stroke, we will assess motor functions, analyze sub-region volume, and address the importance of the contralateral striatum by assessing behavior changes after acute pharmacological inactivation of the contralateral striatum.
Aim 2 will test the hypothesis that the BDNFMet allele induces synaptic changes and shifts synaptic balance to an excitatory status in the striatum. Detailed neuronal morphology and changes in synaptic properties will be investigated. We have shown that BDNFMet/Met mice display increased expression of the inflammatory receptor CD36, which functions in innate immunity and wound healing, and also of its ligand thrombospondins (TSPs) that are involved in the formation of excitatory synapses. We will therefore test the hypothesis that the CD36 pathway contributes to BDNFMet allele-induced synaptic plasticity and motor recovery through synaptic excitation in the contralateral striatum in Aim 3. CD36, TSPs, excitatory and inhibitory synaptic markers will be assessed in WT and BDNFMet/Met mice following stroke. The importance of CD36 in BDNFMet allele-induced brain plasticity will be addressed in BDNFMet/Met mice that lack CD36 or in mice that have been treated with a CD36 antagonist. The insight gained from the studies will provide a means to predict the course of stroke recovery relevant to BDNF SNP carriers. In addition, defining a critical window for activating the CD36 pathway may lead to therapeutic strategies for promoting motor recovery in stroke patients who do not carry the SNP.

Public Health Relevance

Stroke is the leading cause of long-term disability in the American population. This study will investigate whether a mutation in the brain-derived neurotrophic factor (BDNF) gene affects long-term motor recovery following ischemic stroke and whether the effect occurs through an inflammatory receptor, CD36. Understanding the brain mechanisms involved in improving functional recovery will help to predict the course of recovery in stroke patients with the BDNF mutation and lead to potential therapeutic interventions.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Bosetti, Francesca
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Winifred Masterson Burke Med Research Institute
White Plains
United States
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Kim, Eun-Hee; Tolhurst, Aaron T; Szeto, Hazel H et al. (2015) Targeting CD36-mediated inflammation reduces acute brain injury in transient, but not permanent, ischemic stroke. CNS Neurosci Ther 21:385-91
Qin, Luye; Jing, Deqiang; Parauda, Sarah et al. (2014) An adaptive role for BDNF Val66Met polymorphism in motor recovery in chronic stroke. J Neurosci 34:2493-502