In this study, we investigated the roles of BDNF in human cognition and in cognitive dysfunction among schizophrenia patients. Using a large sample of healthy volunteers and schizophrenia patients, we systematically examined the effects of BDNF Val66Met gene polymorphism on a comprehensive battery of standardized neuropsychological tests, and on high-resolution MRI gray matter (GM) brain volume measures. Besides replicating the association between BDNFMet
variant and poor declarative memory 9–12, 14, 15
, we also found BDNFMet
variant to correlate with reduced GM volumes within brain regions known to participate in verbal memory and visuospatial abilities 34–36
. The consonance of these cognitive and brain morphology findings suggests that BDNF val66met polymorphism influences specific aspects of human cognition. Genotype status did not appear to impact general intellectual abilities, or affect attention, problem solving or language skills. Of greater potential significance, we believe, is that BDNFMet
variant may have a specific role for conferring visuospatial dysfunction in schizophrenia. Unlike healthy volunteers, Met-allele-carrier patients consistently performed worse than their Val homozygous counterparts on all four tests of visuospatial abilities. Met-allele-carrier patients also had GM brain volumetric deficits in both the ventral as well as the dorsal visual pathways.
Neurocognitive impairment, a hallmark of schizophrenia 37–40
, is not restricted to a small subset of patients. Measurable deficits are present in 40%–60% of schizophrenia patients 41
. Impairment tends to be generalized and involves dysfunction in multiple cognitive domains including visuospatial abilities 42
. A recent meta-analysis found that compared to healthy volunteers, the mean effect sizes for impairment in Judgment of Line Orientation and WAIS Block Design tests were 0.60 and 0.46 respectively 43
. Such deficits in visuospatial performance have often been attributed to failures of attention or short-term visual memory 44, 45
. However, impairment in the perception of visual stimuli 46
and in other early-stage processing of visual information 47–52
may also contribute to poor visuospatial abilities. Visuospatial performance is subserved by large-scale, distributed neuronal networks. Object perception involves the ventral occipito-temporal pathway whereas the dorsal occipito-parietal stream is associated with spatial information 34, 36, 53, 54
. Therefore, brain regions that mediate visuospatial abilities include the secondary visual cortices (BA 18), inferior temporal regions (BA 37) and the parietal heteromodal association cortices.
In our study, we found that Met allele carriers, regardless of healthy volunteers or schizophrenia patients, had smaller occipital and temporal lobar GM volumes than their respective Val homozygous counterparts. Additionally, from our VBM analyses, Met-allele-carrier patients had smaller left supramarginal gyral GM volume than Val homozygous patients. Healthy volunteers, on the other hand, did not show any parietal GM volume differences across genotype groupings. Because visuospatial abilities involve widely distributed neural circuits, healthy volunteers with BDNFMet variant may have sufficient cognitive reserve to compensate for deficits within the occipital and temporal lobes. Thus, without parietal GM volume deficits, Met-allele-carrier healthy volunteers were able to perform comparably as their Val/Val counterparts in neuropsychological tests assessing visuospatial abilities. On the other hand, having deficits in both the ventral occipito-temporal as well as dorsal occipito-parietal visual pathways, met-allele-carrier schizophrenia patients may be less able to compensate for global reductions in occipital and temporal lobar GM volumes. This may, in turn, translate into poorer performance on neuropsychological tests assessing visuospatial abilities.
Among its diverse functions of neuronal survival and in mediating synaptic plasticity, BDNF is also known to play important roles during the development of the visual cortex 55
as well as in modulating visual functions 56–59
. Visual experience-regulated secretion of BDNF is an essential molecular signal for normal visual cortical maturation. High levels of BDNF and TrkB mRNA expression have been found in the higher-order visual areas of adult macaque monkeys, which further suggest that BDNF may continue to regulate visual functions beyond neurodevelopment. While the importance of BDNF in mediating visual cortical neuronal survival and synaptic plasticity within visual pathways is well established, how would a single nucleotide substitution in the gene encoding the proBDNF protein affect cognitive abilities and GM brain volumes?
As with other neurotrophins, the BDNF gene encodes a precursor peptide (proBDNF). During intracellular trafficking through the Golgi apparatus and trans-Golgi network, the proBDNF domain is subsequently cleaved off so that the remaining mature BDNF protein is packaged into secretory vesicles. Compared to the wild-type BDNF (BDNFVal
), there is relatively less efficient localization of mature BDNF to secretory vesicles when hippocampal neurons 9
or cerebral cortical neurons 13
were transfected with BDNFMet
variant. Since pro-neurotrophins are important for proper folding, dimerization and targeting of the mature neurotrophins 60
, Egan et al and Chen et al 9, 13
have postulated that substitution of valine with methionine in the proBDNF may result in defective intracellular protein trafficking, and perturb BDNF synthesis. This would, in turn, lead to decreased activity-dependent BDNF secretion and impairment in hippocampus-mediated memory functions. Like others 9–11, 14, 15
, we also found BDNFMet
variant to be associated with poorer declarative memory and reduced temporal lobar GM volumes. Although similar expression studies 9, 13
have not been performed on neurons from the visual brain regions, it is not inconceivable that BDNFMet
variant could cause analogous intracellular protein trafficking defects in neurons within distributed neural circuits subserving visuospatial abilities. With less BDNF available for activity-dependent secretion in neurons from all three nodes of the visuospatial neural circuits (i.e. occipital, temporal and
parietal), Met-allele-carrier patients may therefore show greater impairment in visuospatial test performance.
The mechanisms by which BDNFMet
variant affects GM brain volumes are not well understood. This may be mediated neurodevelopmentally through the neurotrophic effects of BDNF 61
. If BDNFMet
variant results in reduced BDNF synthesis, neuronal proliferation and neuronal survival may be decreased in a BDNF-deficient milieu. Besides having fewer neurons, the surviving neurons may also have small soma size and diminished dendritic growth 62
, which would further contribute to smaller gross GM brain volumes. Alternatively, BDNFMet
variant may influence GM brain volumes beyond neurodevelopment through modulating synaptic activity in mature neurons 63
To our knowledge, this is the first study showing that the effects of a common SNP on cognitive function in schizophrenia patients may be different from those in healthy volunteers. Among SNPs known to contribute to variance in human cognition, polymorphisms in the cathecol-O-methyltransferase (COMT), BDNF, metobotropic glutamate receptor (GRM3) and disrupted-in-schizophrenia 1 (DISC1) genes appear to have similar effects in healthy volunteers and in schizophrenia patients 9, 64–67
. None of these previous studies have found significant genotype-by-diagnostic grouping effects with regard to working memory or verbal memory. Clearly, our finding that BDNFMet
variant may have a specific role for conferring visuospatial dysfunction in schizophrenia needs replication.
Our study is also limited by the inherent low specificity of standardized neuropsychological tests to isolate individual cognitive processes. Future studies may want to explore BDNF genotype effects on experimental cognitive tasks (e.g. visual backward masking), where sub-processes within the visual information processing stream could be better isolated. Additionally, our Talairach-atlas based MR image analyses tested hypotheses at the level of cerebral lobes, and may miss smaller brain regions. We addressed the low regional specificity of Talairach-based lobar GM measurements by performing a second set of MR image analyses using optimized VBM. With our VBM analyses, we were able to replicate two previous studies which examined MRI brain morphometric correlates of BDNF val66met polymorphism 14, 15
. Pezawas et al study found reduced GM volumes in the prefrontal regions and smaller hippocampus volumes among Met-allele-carrier healthy volunteers 14
. Szeszko and colleagues reported of smaller hippocampus volumes among Met-allele-carriers and that the genotype effect on hippocampus volume was greater among schizophrenia patients than in healthy volunteers 15
. Our VBM analyses also indicate that brain regions important in verbal memory that are impacted by BDNFMet
variant may be different across diagnostic groups. Met-allele-carrier healthy volunteers had relatively smaller left inferior temporal and left superior frontal gyral GM volumes. Met-allele-carrier patients, on the other hand, only had smaller left parahippocampal gyrus. The absence of frontal lobe GM volume differences between patient genotype groupings may be related to the complex genetics and heterogeneity of schizophrenia. Other schizophrenia susceptibility genes 68
may have greater effects on reducing frontal lobe volume than BDNF val66met polymorphism, thereby obscuring the influence of BDNFMet
variant on reducing prefrontal GM volume among schizophrenia patients. Additionally, the limitations of VBM analytic methods 69, 70
and our choice of VBM analysis may have also contributed to these observed differences in brain regions associated with Met allele across patients and healthy volunteers.
Our findings of BDNFMet
variant associated verbal memory and visuospatial impairment may have potential treatment implications in schizophrenia. Since the greater part of persistent psychosocial impairment in schizophrenia patients is attributable to cognitive deficits 71
, there has been increased interest in developing novel treatments that specifically target neurocognitive dysfunction 72
. It is hoped that cognition enhancing treatments may then translate into improved social and vocational outcome for schizophrenia patients. Thus, BDNF and its receptors (i.e. tyrosine kinase receptor TrkB and p75) are potential molecular targets for developing treatments specific against cognitive dysfunction in schizophrenia. Strategies for exploiting this potential include pharmacological agents that elevate endogenous BDNF 73
, BDNF-mimetic peptides 74
, implantation of genetically engineered cells that produce and release BDNF, or intrathecal infusion of recombinant BDNF. Such novel treatments targeting BDNF transmission may have a small effect on enhancing cognition, and could be especially beneficial for Met-allele-carrier patients. Although many hurdles will need to be overcome before such strategies will benefit patients clinically, it is hoped that as we gradually chip away at the genetic complexity and phenotypic heterogeneity of schizophrenia, individually-tailored and biologically-informed therapies of greater precision will replace our current approaches to the pharmacological treatment of schizophrenia.