**1. Introduction**

The neurotrophin BDNF is one of the most studied and well characterized neurotrophic factors in the CNS. It regulates many different cellular processes involved in the development and maintenance of normal brain function by binding and activating the TrkB, a member of the larger family of Trk receptors. In the brain, BDNF is expressed by glutamatergic neurons [1], glial cells, such as astrocytes isolated from the cortex and hippocampus, but not from the striatum [2], and microglia [3]. During embryogenesis, BDNF–TrkB signaling promotes the differentiation of cortical progenitor cells and later promotes differentiation of cortical progenitor cells into neurons (i.e., neurogenesis) [4]. Several lines of evidence also suggest that the BDNF/TrkB signaling is involved in adult neurogenesis in the hippocampus with differing effects in the dentate gyrus (DG) and subventricular zone (SVZ) [5]. Adult neurogenesis in the dentate gyrus is enhanced by voluntary exercise, exposure to an enriched environment, and chronic antidepressant administration. Recently, it has also been proposed that caloric restriction and intermittent fasting in particular, appears to positively modulate hippocampal neurogenesis and BDNF [6]. The connection between BDNF and the modulation of hippocampal neurogenesis by external stimuli is a topic that has been extensively studied in recent years [7]. It has been demonstrated that voluntary physical exercise, like an enriched environment, increases expression of BDNF in the hippocampus [8], as well as hippocampal neurogenesis [9]. Physical exercise is one particularly effective strategy for increasing circulating levels of BDNF [10,11] and improving brain function [12–14].

In addition, studies also show that BDNF is an important regulator of synaptic transmission and long-term potentiation (LTP) in the hippocampus and in other brain regions. The effects of BDNF on LTP are mediated by the TrkB receptor. Especially in the hippocampus, this neurotrophin is thought to act on both the pre- and post-synaptic compartments, modulating synaptic efficacy, either by changing the pre-synaptic transmitter release, or by increasing post-synaptic transmitter sensitivity [15,16] to induce a long-lasting increase in synaptic plasticity. Additionally, converging data now suggest a role for BDNF in the pathophysiology of brain-associated illnesses. Deficits in BDNF signaling are reported to contribute to the pathogenesis of several major diseases, such as Huntington's disease, Alzheimer's disease (AD), depression, schizophrenia, bipolar, and anxiety disorders. Thus, manipulating the BDNF signaling may present a viable approach to treat a variety of neurological and psychiatric disorders. BDNF protein is also detectable outside of the nervous system in several non-neuronal tissues, such as in endothelial cells [17,18], cardiomyocytes [19], vascular smooth muscle cells [17], leukocytes [20], platelets [21,22], and megakaryocytes [19]. Therefore, it may also be involved in cancer, angiogenesis, reduction of glucose production from the liver [23], and in the uptake of glucose in peripheral tissues (see [24] for review). In addition, BDNF promotes the development of neuromuscular synapses and is required for fiber-type specification, suggesting a potential role as a therapeutic target in muscle diseases [25]. In this review, first we examine the currently known mechanisms of BDNF signaling, information essential for the creation of BDNF-based therapeutics. Next, we focus on the effects of antidepressants on BDNF-mediated plasticity. Additionally, we highlight the function of BDNF as a potent factor capable of conferring protection against neurodegeneration. Finally, we touch on the newly emerging role of BDNF in the pathogenesis of brain gliomas.
