Bdnf La Neurogenesis Postnatal

Cerebral Cortex May 2010;20:1254--1262
doi:10.1093/cercor/bhp189
Advance Access publication September 10, 2009

BDNF Val66Met Polymorphism Influences
Motor System Function in the Human Brain

Stephanie A. McHughen1, Paul F. Rodriguez2, Jeffrey A. Kleim3,
Erin D. Kleim3, Laura Marchal Crespo4, Vincent Procaccio5
and Steven C. Cramer1,6
Departments of 1Anatomy and Neurobiology, 2CognitiveScience, University of California, Irvine, CA 92697, USA,
3
Department of Neuroscience, McKnight Brain Institute,
University of Florida, Brain Rehabilitation Research Center,
Malcom Randall VA Hospital, Gainesville, FL 32610-0244, USA,
Departments of 4Mechanical & Aerospace Engineering,
5
Pediatrics (Human Genetics Division and Metabolism) and
6
Neurology, University of California,Irvine, CA 92697, USA

Keywords: cortex, fMRI, genetics, genotype, plasticity

Introduction
Brain-derived neurotrophic factor (BDNF) is the most abundant
neurotrophin in the brain and is highly expressed throughout
the central nervous system (CNS). This growth factor influences a wide range of brain events related to plasticity and
repair (Cotman and Berchtold 2002). A single nucleotidepolymorphism in the human BDNF gene at codon 66 (val66met)
is present in one or both alleles in approximately 30% of people
in the United States (Shimizu et al. 2004). The current study
examined the effects of this BDNF polymorphism in relation to
human brain motor system function, short-term plasticity, and
motor learning.
The first goal of the current study was to define the effects
that theval66met polymorphism has on brain motor system
function, via functional magnetic resonance imaging (fMRI).
Two competing hypotheses were tested using a brief (4-min)
probe of the motor system. On the one hand, few effects might
be expected as the val66met polymorphism affects activitydependent, rather than constitutive, BDNF secretion (Egan
et al. 2003), and more than 4 min are required for BDNFto
undergo activity-dependent release and to then exert its
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effects. On the other hand, significant polymorphism effects
might be seen with this probe as anatomical studies have found
hippocampal and cortical atrophy in association with thispolymorphism (Pezawas et al. 2004; Szeszko et al. 2005; Bueller
et al. 2006; Ho et al. 2006; Frodl et al. 2007; Toro et al. 2009),
and this suggests that polymorphism effects can be cumulative
over time and thus might become apparent with even a brief
probe of motor system function.
A second goal of this study was to examine the effect that
this BDNF polymorphism has on human brainshort-term
plasticity, using both fMRI and behavioral endpoints. Functional
neuroimaging studies have examined this issue in primary
motor cortex, where the val66met polymorphism was found to
be associated with deficient activity-dependent cortical plasticity over 30 min of motor training (Kleim et al. 2006) and
with reduced after-effects of several repetitive transcranial
magnetic stimulation (TMS)perturbations (Cheeran et al.
2008). However, after 30 min of activity, activity-dependent
BDNF level increases are seen in multiple brain regions, beyond
primary motor cortex (Ploughman et al. 2005), and so evidence
for a polymorphism-related effect would be expected diffusely.
The fMRI has established value for measuring the plasticity of
representational maps throughout the brain across ashort
period of motor activity (Karni et al. 1995; Morgen et al. 2004;
Floyer-Lea and Matthews 2005) and for measuring effects of
genetic polymorphisms (Bookheimer et al. 2000; Egan et al.
2003; Hariri et al. 2003), and so was used in the current study
for examining these issues. The reduced activity-dependent
BDNF release associated with the val66met polymorphism
might be expected to be...