Activin Signaling in the Pathogenesis and Therapy of Neuropsychiatric Diseases

Abstract

Activins are members of the transforming growth factor β (TGFβ) family and serve as multifunctional regulatory proteins in many tissues and organs. In the brain, activin A, which is formed by two disulfide-linked βA subunits, is recognized as the predominant player in activin signaling. Over the last years, considerable progress has been made in elucidating novel and unexpected functions of activin in the normal and diseased brain and in deciphering the underlying molecular mechanisms. Initially identified as a neurotrophic and protective factor during development and in several forms of acute injury, the scope of effects of activin A in the adult central nervous system (CNS) has been considerably broadened by now. Here, we will highlight recent findings that bear significance for a better understanding of the pathogenesis of various neuropsychiatric diseases and might hold promise for novel therapeutic strategies. While the basal level of activin A in the adult brain is low, significant short-term up-regulation occurs in response to increased neuronal activity. In fact, brief exposure to an enriched environment (EE) is already sufficient to considerably strengthen activin signaling. Enhancement of this pathway tunes the performance of glutamatergic and GABAergic synapses in a fashion that impacts on cognitive functions and affective behavior, counteracts death-inducing signals through extrasynaptic NMDA receptors (NMDARs), and stimulates adult neurogenesis in the hippocampus. We will discuss how impaired activin signaling is involved in anxiety disorders, depression, drug dependence, and neurodegenerative diseases such as Alzheimer's and Parkinson's, and how reinforcement of activin signaling might be exploited for therapeutic interventions.

Keywords: activin; anxiety disorders; depression; drug craving; neurodegenerative disease.

Figure 1

Schematic drawing of canonical activin receptor signaling via SMAD2/3 proteins. Note that SMAD2/3 signaling is strictly regulated by extracellular inhibitors like follistatin and inhibin, transmembrane antagonists such as BAMBI and PMEPA1, the cytoplasmatic inhibitory SMAD7 and several transcriptional repressors including SKI, SKIL and TGIF2 in the nucleus. All inhibitors are colored in red. For further explanation see text.

Figure 2

Schematic model of how environmental enrichment (EE) and electroconvulsive therapy (ECT) may produce epigenetic modification through enhanced activin signaling and transcription of the activin target gene Kdm6b. KDM6B acts as a histone demethylase thereby promoting gene expression of transcriptionally repressed genes. Background: in situ hybridization of coronal mouse brain section showing pronounced increase in Inhba mRNA level in dentate gyrus (DG) 2 h after ECT-like electrical stimulation.