LAUSR

There has been stunning progress in depression research, which is reflected in the pages of this special issue of Molecular Psychiatry. Our last special issue was dedicated to stress and behavior; that is one of the key biological pathways leading to depression. Building on our previous special issue, this issue directly addresses depression. This special depression issue has three articles by the late Nobel laureate Paul Greengard. In the first of those papers, Sagi et al. focus on parvalbumin interneurons, which are a major class of GABAergic neurons, essential for hippocampal dentate gyrus (DG) function [1]. They demonstrated, in mice, that hippocampal parvalbumin interneurons express functionally silent serotonin 5A receptors, which translocate to the cell membrane and become active upon chronic, but not acute, treatment with a selective serotonin reuptake inhibitor (SSRI). Activation of these serotonergic receptors in these neurons initiates a signaling cascade through which Gi-protein reduces cAMP levels and attenuates protein kinase A and protein phosphatase 2A activities. This results in increased phosphorylation and inhibition of Kv3.1β channels, and thereby reduces the firing of the parvalbumin neurons. Through the loss of this signaling pathway in these neurons, conditional deletion of the serotonin 5A receptor leads to the loss of the physiological and behavioral responses to chronic antidepressants. This illustrates the mechanisms by which serotonergic signaling in DG mediates the effects of antidepressant treatment. The second paper addresses the biological underpinnings of the delayed onset of action of antidepressants, a topic of perennial interest in depression research. The elucidation of those mechanisms might herald the onset of newer, faster acting antidepressants. Oh et al. propose that this therapeutic delay suggests slow adaptive changes in multiple neuronal subtypes and their neural circuits over prolonged periods of drug treatment [2]. They showed that neuronal activity of hippocampal mossy cells, which are excitatory neurons in the dentate hilus that regulate dentate gyrus activity and function, is enhanced by chronic, but not acute, SSRI administration. Their data established that mossy cells play a crucial role in mediating the effects of chronic antidepressant medication, and their results indicate that compounds that target mossy cell activity would be attractive candidates for the development of new antidepressant medications. In the third paper coauthored by Paul Greengard in this issue, Shuto et al. demonstrated that dopamine D1 receptors in the DG act as a pivotal mediator of antidepressant actions in mice and indicate that stimulation of D1 receptors in the dentate gyrus is a potential adjunctive approach to improve therapeutic efficacy of SSRI antidepressants [3]. The work by Greengard and collaborators is accompanied by other outstanding papers. Teissier et al. examined changes induced by the stress of chronic maternal separation during the first 2 weeks of postnatal life [4]. They showed that unbiased mRNA expression profiling in the medial PFC (mPFC) of maternally separated (MS) pups identified an increased expression of myelin-related genes and a decreased expression of immediate early genes. Bidirectional manipulation of neuron excitability in the mPFC during the P2-P14 period had long lasting effects on adult emotional behaviors and on temporal object recognition. These results identify neuronal activity as a critical target of early-life stress and demonstrate its function in controlling both postnatal oligodendrogenesis and adult mPFC-related behaviors. Most papers in this issue pursue new mechanistic targets with potential impact on depression biology and therapeutics. The paper by Zhang et al. explores the potential role of circRNAs in major depressive disorder (MDD), showing that circular RNA DYM (circDYM) levels were decreased both in the peripheral blood of patients with * Julio Licinio [email protected]