From synapse to nucleus: novel targets for treating depression

Abstract

The need for newer compounds to treat depression is an ever-growing concern due to the enormous societal and financial ramifications of this disorder. Here, we review some of the candidate systems that could potentially be involved in depression, or an inherent resistance to depression termed resilience, and the numerous protein targets for these systems. A substantial body of literature provides strong evidence that neurotrophic factors, glutamate receptors, hypothalamic feeding peptides, nuclear hormone receptors, and epigenetic mechanisms, among others, will make for interesting targets when examining depressive behavior or resilience in preclinical models, and eventually clinical trials. Although some of these targets for depression already appear promising, new waves of more selective compounds for any molecular system should promote a better understanding of this complex disease and perhaps improved treatments.

Figure 1

Emerging antidepressant targets from neurotrophic and glutamatergic signaling pathways. Negative modulators of downstream neurotrophic signaling acting at SPROUTY and SPRED protein families represent potential mechanisms for increasing neurotrophic function. AMPA receptor potentiators and NMDA receptor allosteric modulators (with specific subunit selectivity) are now in clinical trials. Allosteric modulators of mGluRs are also being explored in preclinical studies. Modulators of AMPA receptor expression and function, such as TARPs and CNIH, represent potential therapeutic targets as well. Compounds under development for their antidepressants effect are shown in blue boxes. New target proteins are highlighted in red boxes. CNIH, cornichon homolog; MAPK, mitogen-activated protein kinase; RTK, receptor tyrosine kinase; TARP, transmembrane AMPAR regulatory proteins; VGLUT, vesicular glutamate transporter.

Figure 2

Portrayed here is a molecular pathway analysis of genes regulated in the mouse nucleus accumbens by a direct infusion of the HDAC inhibitor MS-275 after chronic social defeat stress. Infusion of MS-275 promotes antidepressant-like behavioral responses and significantly regulates genes as revealed by microarray analysis. Examples of highly regulated molecular pathways that may provide novel targets for treating depression include genes that encode presynaptic vesicular proteins, plasma membrane receptors, intracellular signaling molecules, proteins that regulate the actin cytoskeleton, and the transcriptional regulatory machinery. Reprinted with permission from The Journal of Neuroscience (Covington et al., 2009).