Genetics of stroke recovery: BDNF val66met polymorphism in stroke recovery and its interaction with aging

Abstract

Stroke leads to long term sensory, motor and cognitive impairments. Most patients experience some degree of spontaneous recovery which is mostly incomplete and varying greatly among individuals. The variation in recovery outcomes has been attributed to numerous factors including lesion size, corticospinal tract integrity, age, gender and race. It is well accepted that genetics play a crucial role in stroke incidence and accumulating evidence suggests that it is also a significant determinant in recovery. Among the number of genes and variations implicated in stroke recovery the val66met single nucleotide polymorphism (SNP) in the BDNF gene influences post-stroke plasticity in the most significant ways. Val66met is the most well characterized BDNF SNP and is common (40-50 % in Asian and 25-32% in Caucasian populations) in humans. It reduces activity-dependent BDNF release, dampens cortical plasticity and is implicated in numerous diseases. Earlier studies on the effects of val66met on stroke outcome and recovery presented primarily a maladaptive role. Novel findings however indicate a much more intricate interaction between val66met and stroke recovery which appears to be influenced by lesion location, post-stroke stage and age. This review will focus on the role of BDNF and val66met SNP in relation to stroke recovery and try to identify potential pathophysiologic mechanisms involved. The effects of age on val66met associated alterations in plasticity and potential consequences in terms of stroke are also discussed.

Keywords: BDNF; Recovery; Stroke; val66met.

FIGURE 1.

Proposed mechanisms that underlie BDNF val66met SNP effect in cortical (A) and subcortical (B) stroke: A, Stroke causes imbalance in excitability (Red arrows) and inter hemispheric inhibition (blue arrows) in Val/Val individuals. Inhibition from the lesioned hemisphere is reduced leading to increased excitability on intact hemisphere. This in turn exerts increased inhibition on to the ipsilesional hemisphere in the intact hemisphere, resulting in a greater extent of cortical imbalance. In Met carriers, cortical excitability in the intact hemisphere is not drastically increased. Similarly, excitability in the lesioned hemisphere is not dampened to a great extent. These observations suggest a milder imbalance in intercortical inhibition. B, Subcortical lesions disturb ipsilesional strio-thalamo-cortical circuits (Cirle and arrow) and cause shrinkage in ipsilateral and contra lateral striatum in val/val carriers. Met carrier mice display enhanced activation in the strio-thalamo-cortical circuits. The excitatory shift may underlie the functional improvement of BDNF^M/M mice and resistant to atrophy in the contralesional striatum.. - * (Helm et al., 2016) , ** (Kim et al., 2016b) ,*** (Kim et al., 2016c)