A new aspect of the TrkB signaling pathway in neural plasticity

Abstract

In the central nervous system (CNS), the expression of molecules is strictly regulated during development. Control of the spatiotemporal expression of molecules is a mechanism not only to construct the functional neuronal network but also to adjust the network in response to new information from outside of the individual, i.e., through learning and memory. Among the functional molecules in the CNS, one of the best-studied groups is the neurotrophins, which are nerve growth factor (NGF)-related gene family molecules. Neurotrophins include NGF, brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and NT-4/5 in the mammal. Among neurotrophins and their receptors, BDNF and tropomyosin-related kinases B (TrkB) are enriched in the CNS. In the CNS, the BDNF-TrkB signaling pathway fulfills a wide variety of functions throughout life, such as cell survival, migration, outgrowth of axons and dendrites, synaptogenesis, synaptic transmission, and remodeling of synapses. Although the same ligand and receptor, BDNF and TrkB, act in these various developmental events, we do not yet understand what kind of mechanism provokes the functional multiplicity of the BDNF-TrkB signaling pathway. In this review, we discuss the mechanism that elicits the variety of functions performed by the BDNF-TrkB signaling pathway in the CNS as a tool of pharmacological therapy.

Keywords: Brain-derived neurotrophic factor; development; intracellular signaling; morphology; neural plasticity; neuron-glia interaction; receptor dimerization; truncated TrkB-T1..

Fig. (1). Schematic representation of TrkB isoforms.

(A) Structures of TrkB isoforms are shown. The extracellular domain (i.e., cysteine-rich, leucine-rich, cysteine-rich, and two immunoglobulin-like domains), transmembrane domain, and initial 12 intracellular amino acid sequences are the same as those of T1 and T2. Truncated forms T1 and T2 possess 11 and 9 specific amino acid sequences, respectively. The dotted square indicates the specific sequences of truncated forms of TrkB, shown in B. (B) Comparison of intracellular amino acid sequences of TrkB isoforms. The parts shown in the square are transmembrane domains of TrkB isoforms. Specific amino acid sequences of T1 and T2 are underlined. In A and B, the T2-specific intracellular sequence is reported in the rat cerebellum.

Fig. (2). TrkB signaling pathways.

In the neuron, shown in a dotted square, BDNF induces three TrkB dimers: TK+ homodimer, TK+-T1 heterodimer, and T1 homodimer. The signaling cascade of TK+ homodimer has been well studied. Activation of PLCγ results in the activation of PKC, which promotes synaptic plasticity. Activation of Shc protein induces activation of the PI3K-Akt and Ras-MAP kinase signaling cascades, which regulate cell survival and differentiation, respectively. It is unclear whether TK+-T1 heterodimer can transduce the signals. Furthermore, T1 plays an important role in synaptic transmission, although the mechanism is not understood. Since T1 homodimer has not yet been observed in neurons, further investigation is needed. In the astrocyte, which is shown in a gray square, T1 is a major isoform of TrkB receptors. The binding of BDNF to T1 induces T1 homodimer, which results in the release of Rho GDI1 and the morphological changes of astrocytes. Moreover, T1 is involved in a Ca²⁺ influx in astrocytes. On the other hand, TTIP (truncated TrkB-interacting protein) is a binding protein of T1, but it is not clear whether it transduces the signals.