Basic brain research shows its age.

At the Gonda Neuroscience and Genetics Research Center at UCLA, there is a cafeteria called “The Synapse.” In addition to invoking a meeting place for people encouraging the free exchange of ideas between distinct scientific disciplines, the name of the cafe also refers to the major structure for exchange of information between neurons (the neuronal synapse) and chromosomes (the meiotic chromosomal synapse). In a similar fashion, the last decade has witnessed a dramatic exchange of information between the basic brain science and genetics that is shining a clearer light on the molecular mechanisms of the psychiatric disorders affecting elderly patients and giving new entry-points for future therapies. This special section, on translational research, focuses on the new role of genetics and its ever-morepowerful technologies in the pursuit of understanding of the behavioral afflictions of elderly persons. The dual spectres of anxiety and depression are major burdens for the elderly population. The opening article, by Gershenfeld et al., 1 reviews some basic-science aspects of these disorders, with an eye toward genetic approaches for understanding their etiology and treatment. The authors also review the related molecular roles of thyroid hormone, testosterone, and the neuroimmune system. This overview article inspires newfound respect for the molecular complexity of the nervous system and suggests many new opportunities for therapeutic intervention in the common disorders in geriatric psychiatry. Genomic technologies are opening up fresh vistas for the study of the molecular basis of brain disorders. Microarrays stand proud in this pantheon of achievement, with the capability of surveying the entire genome for the expression changes occurring in disease. However, this technology has been underutilized in exploring the bewildering complexity of gene-expression changes in the psychiatric disorders of elderly patients. In their article, Unger et al. 2 describe experiments in which they scrutinize the genome for differences in gene-expression between the frontal cortex and hippocampus of wild-type and Presenilin-1 transgenic mice. The Presenilin-1 gene has been implicated in Alzheimer disease (AD) through genetic studies in humans, but its effects on the molecular physiology of the brain are poorly understood. The transgenic mice harbored both the wild-type (normal) human Presenilin-1 gene, as well as a mutant version linked to AD. First, the authors showed significant gene-expression differences between the frontal cortex and the hippocampus in control, non-transgenic mice. Furthermore, the bulk of these differences were maintained in engineered mice overexpressing either the wild-type or mutant Presenilin-1 gene. Interestingly, however, the authors also showed that some genes displayed altered ratios of expression between the frontal cortex and hippocampus in the transgenic mice expressing the mutant Presenilin-1 gene, as compared with the controls. Some of these genes had previously been identified by others as playing a role in AD pathology. Clearly, the remaining genes with perturbed expression ratios are “not the usual” suspects, which could lead to intriguing new insights into the possible mechanisms of this disorder. One of the pathological hallmarks of AD is synaptic loss in selectively vulnerable brain regions, such as the hippocampus. Ginsberg 3 probed the molecular basis of these losses by using microarrays to examine gene-expression changes in the dentate gyrus after section of its principal glutamatergic input, the perforant pathway. Close scrutiny of the time-line of the changes after axotomy allowed a detailed picture