In the present study, we investigated the impact of the functional BDNF val66met polymorphism on magnetic resonance spectroscopic markers (NAA/Cre, NAA/Cho, Cho/Cre, and (Glu + Gln)/Cre) in the left hippocampus, left dorsolateral prefrontal, and left posterior frontomedian cortex, as well as on hippocampal volumes and on verbal memory capacity in a group of 158 subjects (66 schizophrenia patients, 45 BD patients, and 47 healthy controls). Our main finding was a significant effect of BDNF genotype on metabolic markers specifically in the left hippocampus. In particular, homozygous carriers of the met-allele exhibited significantly lower NAA/Cre and (Glu + Gln)/Cre metabolic ratios as compared with val/val homozygotes (Fig. ). This effect was confirmed by controlling for identified intervening covariates. Although in the heterozygous val/met group, the mean values of these MRS ratios laid in between the two homozygous groups, no significant effect of the presence of only one met-allele could be detected in this group. Thus, our data suggest that BDNF effects on NAA/Cre and (Glu + Gln)/Cre ratios in the left hippocampus may be specific for (or at least most pronounced in) homozygous carriers of the met-allele. Alternatively, these effects may be present in heterozygotes for the met-allele as well, but may be too small to have reached the level of statistical significance in our sample.
Overall, these MRS results are consistent with previous reports of a significant reduction in left hippocampal NAA/Cre and NAA/Cho levels in carriers of the BDNF rs6265 met-allele [10
]. Thus, we were able to replicate these prior findings in an ethnically homogeneous sample of only caucasians. Furthermore, our data that were acquired in a mixed sample of both healthy subjects and psychiatric patients with psychotic disorders suggest that the observed BDNF genotype effects on MRS markers may be relatively independent of these psychiatric diagnoses as there were no effects of diagnosis on these markers and no genotype x diagnosis interactions. Moreover, our findings provide in vivo evidence for an effect of the functional BDNF polymorphism on glutamate levels in the left human hippocampus, which is consistent with the theory that BDNF may impact NAA via its influence on the glutamate system [6
Our negative MRS finding in the posterior frontomedian cortex seems to contradict the very recent observation of higher NAA levels in the anterior cingulate cortex of met-allele carriers [13
]. The authors interpreted this finding tentatively as an up-regulation of cingulate NAA to compensate decreasing hippocampal NAA in met-allele carriers. Several methodological differences may account for these partially discrepant results, such as the precise placement and the size of MRS voxels, the measurement of absolute versus relative metabolite concentrations and numerical as well as genetic differences between samples. For example, it is unclear whether and to what extent the rather large ACC voxel recorded by Gallinat and colleagues overlaps with our voxel in the posterior frontomedian cortex, which was anatomically precisely defined as (and adjusted to) the (left sided) cingulate cortex located dorsally and posterior to the genu of the corpus callosum along the cingulate sulcus (see [23
], for a very similar voxel positioning, however, centered on the interhemispheric fissure). Functionally, this cortical region has been implicated in adaptive cognitive control of behavior, in particular in background monitoring of the environment for potentially significant sensory events [15
]. Given the fact that BDNF effects on MRS markers appear to be regionally specific (as indicated by the present and other results), this highlights the importance of investigating clearly defined and (presumably) functionally homogeneous brain regions.
With regard to BDNF effects on brain structure, we were unable to replicate prior findings of a hippocampal volume reduction in carriers of the met-allele [12
] as we did not find any effect of BDNF genotype on hippocampal volume. Thus, this negative finding is more consistent with other recent studies which also did not observe BDNF genotype effects on structural volumes of the hippocampus [33
]. While our finding further excludes that the observed BDNF effects on MRS markers might have resulted from confounding differences in hippocampus volume (see [41
]), it is still possible that BDNF may also impact on hippocampal structure, but with lower effect size, which may not be observable in diagnostically heterogeneous samples. Furthermore, the results are compatible with the suggestion that neurochemical MRS markers may be more sensitive to BDNF genotype effects than volumetric measures [41
]. Interestingly, one study showed that the BDNF val66met polymorphism is associated with temporal gray matter loss over 4 years in patients with Bipolar I Disorder [31
]. Hence, it is possible that BDNF effects on brain structure may only be observable in longitudinal studies that assess changes in the course of brain disorders. However, in this context, it is worth to mention that schizophrenia and bipolar affective disorder share in parts a common pathophysiological pathway and display similar symptoms, but differ in the disease course and in the cortical gray matter loss [9
Finally, our finding of a numerical, but nonsignificant effect of BDNF genotype on verbal memory is quite consistent with previous reports of BDNF genotype effects on episodic memory and, to a lesser extent, on verbal memory [5
]. As verbal memory tests like the California Verbal Learning Test (CVLT) and the Verbal Learning Memory Test (VLMT) may (in comparison to episodic memory tests) also impose considerable demands on prefrontal cortical functions, this may explain the lack of statistical significance for BDNF effects on the VLMT in the present study (for a similar discussion see Egan et al. 2003). Given the fact that BDNF is well-known to facilitate LTP, i.e., memory-related processes in the hippocampus [1
], further studies are definitely required to clarify possible effects of BDNF genotype on hippocampus-dependent cognition. A possible bias of these results might be the effects of concomitant medication on cerebral neurochemistry. This phenomenon is being controversially disputed by different authors, and there might be an effect of neuroleptics on cerebral NAA levels [4
], although in the light of other studies, this appears to be unlikely [18
It can further be speculated whether our results are linked to the heritability of our outcome measures. Different studies point toward heritability of hippocampal volumetric measures, hippocampal spectroscopy parameters, and of verbal memory [20
]. Our finding of a BDNF effect in a mixed sample of healthy controls and patients suffering from schizophrenia and BP is indeed compatible with the assumption of heritability of our outcome parameters.
In summary, the present findings provide further evidence for a crucial role of BDNF in hippocampal functioning. In this context, BDNF has been linked to hippocampus-related forms of learning and memory, in particular via its effects on activity-dependent changes in synaptic strength of glutamatergic synapses [3
]. BDNF has been shown both to facilitate glutamate release at the presynapse and to increase postsynaptic glutamate receptor phosphorylation and synthesis [6
]. In consideration of these findings, only recently, it had been hypothesized that BDNF may exert its observed effects on NAA via its influence on the glutamatergic system [41
]. Consistent with this hypothesis, the present results provide first in vivo evidence for an effect of the functional BDNF val66met polymorphism on the glutamate system in human hippocampus. Furthermore, our data suggest that these BDNF effects on NAA and glutamate in the hippocampus may be most pronounced in homozygous carriers of the BDNF met-allele.