Brain-derived neurotrophic factor (BDNF) modulates hippocampal plasticity and hippocampal-dependent memory in cell models and in animals. We examined the effects of a valine (val) to methionine (met) substitution in the 5' pro-region of the human BDNF protein. In human subjects, the met allele was associated with poorer episodic memory, abnormal hippocampal activation assayed with fMRI, and lower hippocampal n-acetyl aspartate (NAA), assayed with MRI spectroscopy. Neurons transfected with met-BDNF-GFP showed lower depolarization-induced secretion, while constitutive secretion was unchanged. Furthermore, met-BDNF-GFP failed to localize to secretory granules or synapses. These results demonstrate a role for BDNF and its val/met polymorphism in human memory and hippocampal function and suggest val/met exerts these effects by impacting intracellular trafficking and activity-dependent secretion of BDNF.

Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Heritability and polygenic predictionIn the EUR sample, the SNP-based heritability (h 2 SNP ) (that is, the proportion of variance in liability attributable to all measured SNPs)

A fundamental characteristic of working memory is that its capacity to handle information is limited. While there have been many brain mapping studies of working memory, the physiological basis of its capacity limitation has not been explained. We identified characteristics of working memory capacity using functional magnetic resonance imaging (fMRI) in healthy subjects. Working memory capacity was studied using a parametric 'n-back' working memory task involving increasing cognitive load and ultimately decreasing task performance. Loci within dorsolateral prefrontal cortex (DLPFC) evinced exclusively an 'inverted-U' shaped neurophysiological response from lowest to highest load, consistent with a capacity-constrained response. Regions outside of DLPFC, in contrast, were more heterogeneous in response and often showed early plateau or continuously increasing responses, which did not reflect capacity constraints. However, sporadic loci, including in the premotor cortex, thalamus and superior parietal lobule, also demonstrated putative capacity-constrained responses, perhaps arising as an upstream effect of DLPFC limitations or as part of a broader network-wide capacity limitation. These results demonstrate that regionally specific nodes within the working memory network are capacity-constrained in the physiological domain, providing a missing link in current explorations of the capacity characteristics of working memory.

Subcortical dopamine D2 receptor (DRD2) signaling is implicated in cognitive processes and brain disorders, but the effect of DRD2 variants remains ambiguous. We measured allelic mRNA expression in postmortem human striatum and prefrontal cortex and then performed single nucleotide polymorphism (SNP) scans of the DRD2 locus. A previously uncharacterized promoter SNP (rs12364283) located in a conserved suppressor region was associated with enhanced DRD2 expression, whereas previously studied DRD2 variants failed to affect expression. Moreover, two frequent intronic SNPs (rs2283265 and rs1076560) decreased expression of DRD2 short splice variant (expressed mainly presynaptically) relative to DRD2 long (postsynaptic), a finding reproduced in vitro by using minigene constructs. Being in strong linkage disequilibrium with each other, both intronic SNPs (but not rs12364283) were also associated with greater activity of striatum and prefrontal cortex measured with fMRI during working memory and with reduced performance in working memory and attentional control tasks in healthy humans. Our results identify regulatory DRD2 polymorphisms that modify mRNA expression and splicing and working memory pathways.allelic expression imbalance ͉ splice variant ͉ promoter polymorphism ͉ brain imaging A lthough genetic factors contribute to central nervous system (CNS) disorders, only a few genes have been identified as unequivocal risk factors. Aberrant subcortical dopamine D2 receptor (DRD2) signaling is implicated in brain disorders such as drug addiction (1, 2), schizophrenia, and Parkinson's disease (3, 4). DRD2 variants Taq1A, promoter polymorphism Ϫ141C del/ins, and a synonymous SNP in exon 7 (C957T) have been associated with schizophrenia and drug abuse (5-8), but associations are not consistently replicated (9-11). Moreover, polymorphisms relevant in vivo remain unknown. Our goal was to identify functional DRD2 polymorphisms linked to CNS functions.DRD2 variants could have maximal impact in the basal ganglia endowed with prominent DRD2 signaling. A crossroad between cortex and dopamine projections from the brainstem, basal ganglia in the caudate and pallidum mediate cognitive processes (12)(13)(14) and contribute to focus of working memory (15). Dopamine-DRD2 signaling in these structures decreases GABA (16, 17) and glutamate inputs to striatal spiny neurons (18). DRD2 density affects working memory performance in mice (19), and striatal DRD2 receptor availability is linked to working memory and attention in humans (20). Another mechanism modulating DRD2 signaling involves alternative splicing of exon 6 to yield DRD2L (long) and DRD2S (short, considered an autoreceptor), expressed mainly postsynaptically and presynaptically, respectively (21, 22). Relative expression of DRD2S and L is critical to dopamine modulation of GABA and glutamate striatal transmission (23, 24).We searched for genetic variants modulating DRD2 neurotransmission in human brain. Because the DRD2 locus lacks frequent nonsynonymous SNPs that alter receptor...