Are BDNF and glucocorticoid activities calibrated?

Abstract

One hypothesis to account for the onset and severity of neurological disorders is the loss of trophic support. Indeed, changes in the levels and activities of brain-derived neurotrophic factor (BDNF) occur in numerous neurodegenerative and neuropsychiatric diseases. A deficit promotes vulnerability whereas a gain of function facilitates recovery by enhancing survival, synapse formation and synaptic plasticity. Implementation of ‘BDNF therapies’, however, faces numerous methodological and pharmacokinetic issues. Identifying BDNF mimetics that activate the BDNF receptor or downstream targets of BDNF signaling represent an alternative approach. One mechanism that shows great promise is to study the interplay of BDNF and glucocorticoid hormones, a major class of natural steroid secreted during stress reactions and in synchrony with circadian rhythms. While small amounts of glucocorticoids support normal brain function, excess stimulation by these steroid hormones precipitate stress-related affective disorders. To date, however, because of the paucity of knowledge of underlying cellular mechanisms, deleterious effects of glucocorticoids are not prevented following extreme stress. In the present review, we will discuss the complementary roles share by BDNF and glucocorticoids in synaptic plasticity, and delineate possible signaling mechanisms mediating these effects.

Brain-Derived Neurotrophic Factor Signaling Rewrites the Glucocorticoid Transcriptome via Glucocorticoid Receptor Phosphorylation

“…Given the communication between glucocorticoid and BDNF signaling in neuronal physiology and stress-associated pathophysiology (27)(28)(29), as well as the coexpression of GR and TrkB in neurons, we sought to understand the genes regulated by both signaling pathways in neurons. We used a microarray approach to determine the genes that were regulated at least 2-fold in primary rat cortical neurons upon treatments with Dex and BDNF alone or in combination (Fig.…”

Regulation of TRH neurons and energy homeostasis-related signals under stress

“…The contradictory results observed between the effects of neonatal stress and those of growing in an enriched environment on the relationship of GR and BDNF (Jeanneteau & Chao 2013) include the responses of the HPA, HPT, and SNA that affect energy balance. Improvements and standardized housing conditions seem required to define adequate controls and obtain reproducible data between different laboratories, together with adequate reports of the animals' age and body weight, as some correspond to the adolescent period (McCutcheon & Marinelli 2009).…”

“…BDNF and its receptor TRKB are expressed in several hypothalamic nuclei including TRHergic cells of the PVN (Ubieta et al 2007). BDNF regulates neurogenesis, neuronal plasticity, and support during development and throughout the animal's life-span (Jeanneteau & Chao 2013). In the hypothalamus, BDNF plays an important part in energy homeostasis (Levin 2007, Rothman et al 2012.…”

Vers une explication des effets mnémoniques des glucocorticoïdes ?

“…Parmi les protéines intermédiaires mises en jeu par la convergence des voies de signalisation du BDNF et des glucocorticoïdes, la phosphatase MKP-1 (mitogen-activated protein [MAP] kinase phosphatase-1), qui désactive la voie de MAP-kinase, facilite le réar-rangement structural des neurones. La persistance d'une expression trop élevée du gène correspondant peut, chez l'homme comme chez la souris, conduire à des troubles du comportement cognitif [27]. Au contraire, l'ablation du gène mkp-1 empêche le réarrangement structural des neurones et protège des effets délétères du stress sur l'apprentissage [28,29].…”

“…À la suite d'un stress sévère, le nombre d'épines éliminées est supérieur au nombre d'épines formées, le résultat pouvant conduire à des déficits cognitifs, des maladies psychiatriques et à un vieillissement prématuré. En effet, les perturbations du rythme circadien de la sécrétion de glucocorticoïdes dans le milieu hormonal sont très fréquentes dans les maladies psychiatriques, et s'aggravent au cours du vieillissement [27,30]. Si le concept est clair, il reste cependant de nombreuses questions à élucider.…”