Neurotrophins are a family of regulatory factors that mediate the differentiation and survival of neurons, as well as the modulation of synaptic transmission and synaptic plasticity (Patapoutian and Reichardt 2001; Poo 2001). The neurotrophin family now includes, among others, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), neurotrophin-4/5 (NT4/5), and neurotrophin-6 (NT6) (Patapoutian and Reichardt 2001). These various proteins are closely related in terms of sequence homology and receptor specificity. They bind to and activate specific tyrosine receptor kinases belonging to the Trk family of receptors, including TrkA, TrkB, and TrkC, and a pan-neurotrophin receptor p75 (Patapoutian and Reichardt 2001; Poo 2001). Additionally, there are two isoforms of TrkB receptors: the full-length TrkB and the truncated form of TrkB, which does not contain the intracellular tyrosine kinase domain (Fryer et al. 1996). The truncated form of TrkB can thus function as a dominant-negative inhibitor for the TrkB receptor tyrosine kinase, thereby providing another mechanism to regulate BDNF signaling in the CNS (Eide and Virshup 2001; Gonzalez et al. 1999).

Neurotrophins can be secreted constitutively or transiently, and often in an activity-dependent manner. Observations support a model in which neurotrophins are generally secreted from the dendrite and act retrogradely at presynaptic terminals, where they act to induce long-lasting modifications (Poo 2001). Within the neurotrophin family, BDNF is a potent physiological survival factor that has also been implicated in a variety of pathophysiological conditions, such as Parkinson's disease, Alzheimer's disease, diabetic peripheral neuropathy, and psychiatric disorders (Malberg et al. 2000; Nagatsu et al. 2000; Pierce and Bari 2001; Salehi et al. 1998). In particular, a genetic variant of BDNF (Val66Met) has been associated with risk for development of mood disorders in humans, as well as with mood- and anxiety-related behaviors and response to antidepressant medications in animal models (Z. Y. Chen et al. 2006; Neves-Pereira et al. 2002; Sklar et al. 2002). Recent data also support a role for this polymorphism in human brain development and function (Frodl et al. 2007; Kleim et al. 2006). The cellular actions of BDNF are mediated through two types of receptors: a high-affinity tyrosine receptor kinase (TrkB) and a low-affinity pan-neurotrophin receptor (p75) (see Figure 1-1 for details). TrkB is preferentially activated by BDNF and NT4/5 and appears to mediate most of the cellular responses to these neurotrophins (Du et al. 2003; Poo 2001).

Binding of BDNF initiates TrkB dimerization and transphosphorylation of tyrosine residues in its cytoplasmic domain (Patapoutian and Reichardt 2001), a process that involves cAMP activation (Ji et al. 2005). Binding of cytoplasmic src homology 2 (SH2) domain-containing scaffolding proteins—including Shc and Grb-2, which recognize specific phosphotyrosine residues on the receptor—can thus result in the recruitment of a variety of effector molecules. This recruitment of effector molecules generally occurs via interaction of proteins with modular binding domains SH2 and SH3 (named after homology to the src oncogenes—src homology domains). The ability of multiple effectors to interact with phosphotyrosines is undoubtedly one of the keys to the pleiotropic effects that neurotrophins can exert. The physiological effects of neurotrophins are mediated by varying degrees of activation of three major signaling pathways—the Ras/MAP kinase pathway, the phosphoinositide-3 kinase (pi3k) pathway, and the phospholipase C-71 (PLC-71) pathway (Figure 1-9). Among these pathways, the effects of the PI3K pathway and the MAP kinase pathway have traditionally been linked to the cell survival effects of neurotrophins (Patapoutian and Reichardt 2001) (see Figure 1-9). A series of studies by Duman (2002) have shown that BDNF and TrkB are upregulated by antidepressant treatment. The "neurotrophin hypothesis of depression" has enjoyed heuristic value in reconceptualizing mood disorders as arising from abnormalities in neural plasticity cascades. The demonstration that decreases in hippocampal BDNF levels are correlated with stress-induced depressive behaviors and that antidepressant treatment enhances BDNF expression has generated considerable interest. It is now accepted that the main function of BDNF in the adult brain is regulating synaptic plasticity rather than mediating neuronal survival. Exciting results show that BDNF is first synthesized as a precursor proBDNF, which is then proteolytically cleaved to mature BDNF (mBDNF). ProBDNF and mBDNF facilitate LTD and LTP, respectively, suggesting opposing cellular functions. Finally, BDNF plays different and perhaps opposing roles in the brain stress versus reward system (discussed in Martinowich et al. 2007).

FIGURE 1-9. Neurotrophic cascades.

Neurotrophic factor

kinase pathway

Copyright © American Psychiatric Publishing, Inc., or American Psychiatric Association, unless otherwise indicated in figure legend. All rights reserved.

Cell survival is dependent on neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor, and the expression of these factors can be induced by synaptic activity. Phosphorylation of tyrosine receptor kinase (Trk) receptors activates a critical signaling pathway, the Ras/MAP kinase pathway (see Figure 1-15). Phosphorylated Trk receptors also recruit the phosphoinositide-3 kinase (PI3K) pathway through at least two distinct pathways, the relative importance of which differs between neuronal subpopulations. In many neurons, Ras-dependent activation of PI3K is the most important pathway through which neurotrophins promote cell survival (not shown; see text). In some cells, as shown in the figure, PI3K can also be directly activated through adaptor proteins (Shc, Grb-2, and Gab-1). PI3K directly regulates certain cytoplasmic apoptotic pathways. Akt phosphorylates the pro-apoptotic Bcl-2 family member BAD (Bcl-xl/Bcl-2-associated death promoter), thereby inhibiting BAD's pro-apoptotic functions (Datta et al. 1997). Akt may also promote survival in an indirect fashion by regulating another major signaling enzyme: glycogen synthase kinase-3 (GSK-3) (Woodgett 2001). Interestingly, lithium is an inhibitor of GSK-3. Phosphorylated Trk receptors also recruit phospholipase C-71 (PLC-71). The Trk kinase then phosphorylates and activates PLC-71, which acts to hydrolyze phosphatidylinositides to generate diacylglycerol (DAG) and inositol-1,'4,5-triphosphate (IP3). Antidepressant medication and mood stabilizers increase levels of BDNF and other neurotrophic factors, suggesting a therapeutic relevance.

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