Mechanisms Controlling the Expression and Secretion of BDNF

Abstract

Brain-derived nerve factor (BDNF), through TrkB receptor activation, is an important modulator for many different physiological and pathological functions in the nervous system. Among them, BDNF plays a crucial role in the development and correct maintenance of brain circuits and synaptic plasticity as well as in neurodegenerative diseases. The proper functioning of the central nervous system depends on the available BDNF concentrations, which are tightly regulated at transcriptional and translational levels but also by its regulated secretion. In this review we summarize the new advances regarding the molecular players involved in BDNF release. In addition, we will address how changes of their levels or function in these proteins have a great impact in those functions modulated by BDNF under physiological and pathological conditions.

Brain-derived neurotrophic factor (BDNF): an effect biomarker of neurodevelopment in human biomonitoring programs

“…The activation of phosphorylated-TrkB receptors after m-BDNF-TrkB binding activates different enzymes, including phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), guanosine triphosphate hydrolases (GTPases) from the Ras homolog (Rho) gene family, and phospholipase C-γ (PLC-γ); which initiates distinct signaling cascades, leading to specific cellular functions ( Reichardt, 2006 ; Bathina and Das, 2015 ; Kowiański et al, 2018 ). MAPK is crucial for the activation of extracellular-signal-regulated kinase 1/2 (ERK 1/2) and cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) which play important roles in cytoskeleton protein synthesis, early response gene expression, branching, and dendritic growth in hippocampal neurons ( Bathina and Das, 2015 ; Arévalo and Deogracias, 2023 ). The PI3K/Akt pathway modulates synaptic plasticity that depends on N-methyl-D-aspartate receptors (NMDAR), while the PI3K/Akt/mTOR pathway enhances dendritic growth and branching by regulating protein synthesis.…”

“…In contrast, the activation of nuclear receptor kappa B (NR-κB) promotes processes that support survival and the maintenance of an optimal number of neuronal cells. Finally, the Ras homolog gene family member A (RhoA) cascade regulates the growth cone of neurons, a crucial structure involved in neurite outgrowth and guidance ( Reichardt, 2006 ; Kowiański et al, 2018 ; Arévalo and Deogracias, 2023 ).…”

Brain-derived neurotrophic factor contributes to activity-induced muscle pain in male but not female mice

“…BDNF in spinal dorsal horn can be produced by primary afferent fibers or microglia [23,71,72]. Genetic studies have started to examine the contributions of primary afferent fibers and microglia on BDNF production and impact.…”

“…For example, in male, but not female mice, application of BDNF increases expression of glutamate receptor GluN2B, decreases expression of the neuron specific chloride extruder KCC2, and potentiates NMDAR excitatory postsynaptic potentials [70]. It should be noted that BDNF receptors are expressed on myocytes and local immune cells like macrophages can also express BDNF and its receptors [23,71,72]. It is therefore also possible that peripheral BDNF is derived from local immune or muscle cells in addition to sensory afferents.…”

Effect of Short Photoperiod on Behavior and Brain Plasticity in Mice Differing in Predisposition to Catalepsy: The Role of BDNF and Serotonin System

“…In its turn, BDNF is crucially involved in the regulation of neuro-, glio-, and synaptogenesis, neuroprotection [ 14 , 15 ], and in the response to stressful events [ 16 , 17 ]. The precursor of BDNF (proBDNF) is enzymatically cleaved, either by intracellular (furin/PC1) or extracellular proteases (tPA/plasmin/MMP), to generate mature BDNF [ 18 ]. Once secreted, BDNF and proBDNF bind to two sets of receptors.…”