Mood disorders

Anxiolytic- and antidepressant-like profiles of the galanin-3 receptor (Gal3) antagonists SNAP 37889 and SNAP 398299. Swanson, C. J. et al. Proc. Acad. Natl Sci. USA 102, 17489–17494 (2005)

Stathmin , a gene enriched in the amygdala, controls both learned and innate fear. Shumyatsky, G. P. et al. Cell 123, 697–709 (2005)

Novel targets for mood disorders have been revealed by two recent papers. In the first, the authors show that galanin, a peptide known to be implicated in anxiety and depression, mediates its effects through the galanin-3 receptor. The authors found that acute administration of two small-molecule Gal3-antagonists to mice improved their social interaction and reduced anxiolytic and depressive behaviours, and worked synergistically with, and in a similar manner to, 5-hydroxytryptamine (5-HT) antagonists. The second paper identified a gene that encodes stathmin, a microtubule-formation inhibitor expressed at high levels in the amygdala and in structures that convey information about learned and innate fear. Stathmin-null mice were less able to learn new fear than wild-type mice and failed to recognize danger. In addition to stathmin's potential as an anti-anxiolytic drug target, ablation of its activity in mice generates a model that could be useful in the development of anti-anxiolytic agents.

Autoimmune disease

Inhibition of FLT3 signaling targets DCs to ameliorate autoimmune disease. Whartenby, K. A. et al. Proc. Acad. Natl Sci. USA 102, 16741–16746 (2005)

Most approaches to treating autoimmune diseases focus on the direct suppression of unregulated autoreactive T cells. The authors of this paper took a different approach by selectively targeting dendritic cells, which are precursors of T cells that differentiate in response to FLT3 ligand. Inhibition of FLT3 signalling using small-molecule tyrosine kinase inhibitors induced apoptosis in mouse and human dendritic cells, and improved established disease in a model of multiple sclerosis.

Neurological diseases

DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Millar, J. K. et al. Science 310, 1187–1191 (2005)

The disrupted in schizophrenia 1 (DISC1) gene has been implicated in schizophrenia and other affective disorders but its role in disease progression is unknown. The authors of this paper have shown that a translocation in the gene encoding phosphodiesterase-4B (PDE4B) also seems to be a candidate susceptibility factor for schizophrenia, and propose that this results from the role of PDEs in the regulation of cAMP, which is involved in learning, memory and mood. Further investigation revealed that DISC1 interacts with a domain of PDE4B and that increasing levels of cAMP causes a dissociation of this complex and resultant increase in PDE4B activity. The authors speculate that genetic variations in these two genes will result in altered cAMP catabolism that manifests as psychiatric disorders.