BDNF and Activity-Dependent Synaptic Modulation

Abstract

Much of the brain's ability to adapt or modify itself in response to experience and environment lies in the plasticity of synaptic connections, both short- and long- terms. Substantial evidence indicates that the number and the strength of synapses can be changed by neuronal activity (Bliss and Collingridge 1993; Linden 1994;Malenka and Nicoll 1999; McEwen 1999). It is now widely accepted that activity-dependent modulation of synapses is critical for brain development as well as many cognitive functions in the adult. Molecular mechanisms that translate patterns of neuronal activity into specific changes in the structures and function of synapses, however, remain largely unknown. A hypothesis was put forward several years ago that neurotrophins may serve as molecular mediators for synaptic plasticity based on two observations: (1) The expression of neurotrophins is regulated by neuroelectric activity; and (2) neurotrophins could modulate the efficacy of synaptic transmission or the growth of dendrites and axons, the structural elements necessary for synaptogenesis (Thoenen 1995; Berninger and Poo 1996; Bonhoeffer 1996;Katz and Shatz 1996; Lu and Figurov 1997). It was proposed that neuronal activity would enhance local synthesis/secretion of neurotrophins, which would in turn regulate synaptic efficacy or growth. This simple idea was very attractive to scientists in both the neurotrophin and plasticity fields. The convergence of the two fields has brought an exciting new area of research—neurotrophic regulation of synapse development and plasticity. There has been a rapid growth of this area in recent years. It is now widely accepted that neurotrophins have a crucial role in synaptic transmission and plasticity. As many growing fields, enthusiastic efforts by scientists with different backgrounds and expertise have generated more questions than answers, and these efforts are likely to bring in many new and unexpected findings.

Neurotrophins belong to a family of secretory proteins that include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4/5. These proteins initiate their biological functions by interacting with their cognate receptors. All neurotrophins bind to the p75 neurotrophin receptor (p75NR) (Chao 1992), and each neurotrophin also binds to a specific Trk receptor tyrosine kinase: NGF binds to TrkA; BDNF and NT-4/5 to TrkB; and NT-3 to TrkC (Barbacid 1993). So far, all the synaptic functions of neurotrophins seem to be mediated by the Trk receptors. Ligand binding results in dimerization and autophosphorylation of the Trk receptors, leading to activation of the tyrosine kinases. Activated receptors in general are capable of triggering a number of signal transduction cascades including the MAPK pathway, the phosphatidylinositol 3-kinase (PI3K) pathway, and the phospholipase C-γ (PLC-γ) pathway (Kaplan and Miller 2000; Patapoutian and Reichardt 2001). These signals then pass on to the nucleus to activate transcription factors that alter gene expression. Although for decades neurotrophins have been viewed as major regulators for neuronal survival and differentiation during embryonic development and maintenance of viability of neurons in adulthood (Levi-Montalcini 1987; Lewin and Barde 1996; Huang and Reichardt 2001), there is no doubt that these factors are also important for the development and function of synapses.

The synaptic function of neurotrophins was first discovered at the neuromuscular junction (NMJ) in vitro. Application of BDNF, or NT3 to the neuromuscular synapses, elicits a rapid enhancement of transmitter release (Lohof et al. 1993; Stoop and Poo 1995). The synthesis of NT3 and secretion of NT4 from the postsynaptic muscle cells increase rapidly in response to presynaptic activity (Wang and Poo 1997; Xie et al. 1997). The acute effect of neurotrophins occurs preferentially to active synapses and requires cAMP as a gate (Boulanger and Poo 1999a,b). Moreover, such regulation requires a cascade of protein phosphorylation events (He et al. 2000; Yang et al. 2001), and is independent of new protein synthesis (Stoop and Poo 1995; Chang and Popov 1999). At hippocampal CA1 synapses, substantial evidence indicates that BDNF acutely facilitates long-term potentiation (LTP) (Korte et al. 1995; Figurov et al. 1996; Patterson et al. 1996). This effect is caused primarily to a presynaptic mechanism (Gottschalk et al. 1998; Xu et al. 2000) and has been attributed to a potentiation of synaptic responses to tetanic stimulation and an enhancement of synaptic vesicle docking, possibly through changes in the levels and/or phosphorylation of synaptic proteins (Gottschalk et al. 1999;Pozzo-Miller et al. 1999; Jovanovic et al. 2000). Postsynaptic effects of BDNF on dentate LTP in slices and on NMDA receptors in cultured hippocampal neurons have also been reported (Levine et al. 1998;Kovalchuk et al. 2002). In the visual cortex, BDNF has been shown to facilitate LTP (Akaneya et al. 1997; Huber et al. 1998; Jiang et al. 2001) and attenuates LTD in layer II/III synapses of young adult rats (Akaneya et al. 1996; Huber et al. 1998; Kinoshita et al. 1999; Kumura et al. 2000).

In addition to their acute effects on synaptic transmission and plasticity, neurotrophins also exhibit a long-term regulatory role in synapse development and function. Long-term application of neurotrophins exerts complex modulation of dendritic and axonal growth in the brain, particularly in the visual system (Cohen-Cory and Fraser 1995; McAllister et al. 1995). Neurotrophins are involved in activity-dependent synaptic competition and formation of ocular dominance columns in the visual cortex (Maffei et al. 1992; Cabelli et al. 1995; Huang et al. 1999). Substantial evidence suggests that neurotrophins promote the maturation of the neuromuscular synapses in vitro and in vivo (Wang et al. 1995; Liou and Fu 1997; Gonzalez et al. 1999; Nick and Ribera 2000). Long-term regulation of synaptic transmission by neurotrophins has also been observed in glutamatergic and GABAergic synapses in the central nervous system (CNS) (Rutherford et al. 1998; Vicario-Abejon et al. 1998; Huang et al. 1999; Sherwood and Lo 1999). Interestingly, the long-term synaptic effects of BDNF in hippocampal slices appear to be dependent on cAMP and new protein synthesis (Tartaglia et al. 2001), characters reminiscent of late phase LTP (L-LTP) and long-term memory seen in many model systems.

The synaptic functions of neurotrophins have been covered in some detail by a number of recent reviews (Lu and Chow 1999; McAllister et al. 1999; Schuman 1999; Poo 2001). This review addresses the relationship between neuronal activity and neurotrophins in synaptic modulation. I have primarily focused on BDNF because it has been studied most extensively. I describe how neuronal activity regulates the transcription of BDNF gene, the transport of BDNF mRNA, and the secretion of BDNF protein. I also discuss evidence for activity-dependent modulation of trafficking of the BDNF receptor, TrkB. Efforts have been made to put complex and sometimes conflicting results into perspective. I believe that these recent studies may provide important insights into how synapse-specific modulation could be achieved by diffusible molecules, such as BDNF.

Possible Mechanisms for Local and SynapseSpecific Modulation by Neurotrophins

The studies described above strongly suggest an intimate relationship between neuronal activity and neurotrophins in the modulation of synapse structures and functions. Thus, neurotrophins have been proposed to mediate activity-dependent synaptic potentiation in the CNS (Thoenen 1995; Berninger and Poo 1996; Bonhoeffer 1996; Katz and Shatz 1996; Lu and Figurov 1997). This hypothesis is particularly attractive for homosynaptic and associative LTPs because it links patterned neuronal activity to molecular signals that control synaptic efficacy and connectivity. To qualify neurotrophins as mediators for these types of synaptic potentiation, however, two key issues must be addressed. First, because many forms of activity-dependent plasticity occur in a local and synapse-specific manner (Stent 1973; Bliss and Collingridge 1993; Linden 1994; Malenka and Nicoll 1999), neurotrophins should act locally to translate the effect of neuronal activity into structural and functional changes in specific synapses. In a number of carefully designed studies, such local and synapse-specific effects of neurotrophins have been demonstrated. For example, whereas focal application of NT3 to any part of motor neurons could elicit acute synaptic potentiation (Chang and Popov 1999), BDNF must be applied to the synapse, not cell body, to elicit its acute effect (Stoop and Poo 1995). When a motor neuron innervates two myocytes, one of which over-expresses NT4, synaptic potentiation is restricted to the NT4-expressing synapses without spreading to the control synapse made by the same presynaptic neuron as close as 60 μm away (Wang et al. 1998). In hippocampal cultures, application of BDNF preferentially potentiates immature synapses with lower release probability without affecting nearby mature synapses (Lessmann and Heumann 1998; Berninger et al. 1999). The effect of BDNF may also be limited to specific postsynaptic targets. In a single excitatory neuron innervating both glutamatergic and GABAergic neurons, BDNF selectively potentiates the synapses with glutamatergic, but not GABAergic, neurons as their postsynaptic partners (Schinder et al. 2000). When two sets of Schaffer collaterals-CA1 synapses in the same hippocampal slice are monitored simultaneously, BDNF treatment potentiates the tetanized pathway without affecting the synaptic efficacy of the untetanized pathway (Gottschalk et al. 1998). These results indicate that BDNF effects could be spatially restricted and selective to certain specific synapses.

The second key issue is how BDNF can act preferentially on active synapses. The widely accepted Hebb's hypothesis predicts that more active synapses are favored during synaptic competition (Stent 1973). If diffusible neurotrophins are to mediate the activity-dependent synaptic potentiation, they must be able to distinguish the active and inactive synapses that are right next to each other. One way to achieve this is to have activity-dependent control of the synaptic responsiveness to neurotrophins. A number of recent experiments suggest that at least for BDNF, this may be a plausible mechanism. For example, presynaptic depolarization greatly facilitates BDNF modulation of synaptic transmission at the neuromuscular junction (Boulanger and Poo 1999b). The survival effect of BDNF on retinal ganglion neurons requires depolarization by high K ^{or glutamate agonists, or an elevation of intracellular cAMP (}Meyer-Franke et al. 1995). In the hippocampus, the effect of BDNF on synaptic responses to repetitive stimulation at CA1 synapses is observed only when presynaptic neurons are stimulated at high frequency (Gottschalk et al. 1998). Moreover, pairing of BDNF with neuronal activity appears to be more effective in inducing long-term synaptic potentiation. At CA1 synapses, weak tetanus induces only short-term potentiation of low magnitude, but strong LTP when paired with BDNF application (Figurov et al. 1996). At dentate synapses, pairing of a brief puff of BDNF with a weak presynaptic stimulation elicits a robust LTP (Kovalchuk et al. 2002). The selective pairing of BDNF and high-frequency neuronal activity could potentially provide the signal for coincidence detection. In the visual cortex, regulation of dendritic arborization in the visual cortex by BDNF requires neuronal activity and Ca ^{influx through NMDA receptors (}McAllister et al. 1996). Taken together, these results support the notion that BDNF preferentially regulates synapses with higher activity levels.

The local and synapse-specific modulation, together with preference in active neurons/synapses, suggests that neurotrophins must preferentially regulate active synapses with little or no effect on nearby less active synapses. As a diffusible molecule, how could BDNF distinguish active and inactive neurons or synapses? In the following sections, I discuss experimental data that demonstrate various ways by which BDNF restricts its biological effects to active synapses. First, the transcription of BDNF could be regulated by neuronal activity (Fig.​(Fig.1A).1A). This phenomenon has been repeatedly observed in the many different populations of neurons in the CNS (Thoenen 1995; McAllister et al. 1999). As transcription must occur in the cell body, BDNF mRNA needs to be either actively transported or passively trapped at specific synapses. Activity-dependent dendritic targeting of BDNF mRNA and its local translation may be one solution for this conundrum (Fig. ​(Fig.1A).1A). Second, activity-dependent secretion of BDNF could occur locally at the site of active synapses, with mechanisms that limit its diffusion (Fig. ​(Fig.1B). BDNF1B). BDNF is a sticky molecule with limited diffusion capacity. Truncated TrkB molecules are highly expressed in the cell surface of mature CNS neurons may also limit BDNF diffusion (Biffo et al. 1995; Fryer et al. 1996; McAllister et al. 1999). Third, active neurons/synapses may respond better to BDNF compared to inactive ones, and this could be achieved by an activity-dependent control of the number of TrkB receptors on the cell surface (Fig. ​(Fig.1C).1C). Cell surface insertion of TrkB receptors appears to be enhanced by excitatory synaptic activity, suggesting local insertion of TrkB at active synapses (Du et al. 2000). Finally, neuronal activity could also facilitate the internalization of BDNF-receptor complex (Fig. ​(Fig.1D),1D), which is a key signaling event that mediates many of the BDNF functions.

Figure 1.

Possible mechanisms to ensure synapse specificity of BDNF modulation. (A) Activity-dependent transcription (1); translocation of mRNA (2); and translation (3). mRNA could be selectively targeted to the active synapse or nonselectively translocated to dendrites, but trapped by an active spine. (B) Activity-dependent secretion. BDNF is secreted locally at or near active synapses and its diffusion is limited by truncated TrkB (TrkB-T1). (C) Activity-dependent insertion of TrkB receptor on cell surface. Neuronal/synaptic activity induces Ca ^{influx, leading to fusion of TrkB containing vesicles to the cell membranes. (}D) Activity-dependent internalization of TrkB receptor. Activity and Ca ^{enhance TrkB receptor tyrosine kinase, which in turn facilitates ligand-induced internalization of TrkB.}

Acknowledgments

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