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A simple role for BDNF in learning and memory?

Cunha C, Brambilla R, Thomas KL - Front Mol Neurosci (2010)

Bottom Line: More recently, BDNF has also emerged as an important regulator of synaptogenesis and synaptic plasticity mechanisms underlying learning and memory in the adult CNS.We will show that maturation of BDNF, its cellular localization and its ability to regulate both excitatory and inhibitory synapses in the CNS may result in conflicting alterations in synaptic plasticity and memory formation.Lack of a precise knowledge about the mechanisms by which BDNF influences higher cognitive functions and complex behaviours may constitute a severe limitation in the possibility to devise BDNF-based therapeutics for human disorders of the CNS.

View Article: PubMed Central - PubMed

Affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca Milan, Italy.

ABSTRACT
Since its discovery almost three decades ago, the secreted neurotrophin brain-derived neurotrophic factor (BDNF) has been firmly implicated in the differentiation and survival of neurons of the CNS. More recently, BDNF has also emerged as an important regulator of synaptogenesis and synaptic plasticity mechanisms underlying learning and memory in the adult CNS. In this review we will discuss our knowledge about the multiple intracellular signalling pathways activated by BDNF, and the role of this neurotrophin in long-term synaptic plasticity and memory formation as well as in synaptogenesis. We will show that maturation of BDNF, its cellular localization and its ability to regulate both excitatory and inhibitory synapses in the CNS may result in conflicting alterations in synaptic plasticity and memory formation. Lack of a precise knowledge about the mechanisms by which BDNF influences higher cognitive functions and complex behaviours may constitute a severe limitation in the possibility to devise BDNF-based therapeutics for human disorders of the CNS.

No MeSH data available.


Related in: MedlinePlus

BDNF processing, packaging and secretion in neurons. BDNF is synthesized as a pre-proBDNF protein, which has its pre-sequence cleaved off in the endoplasmic reticulum (ER). The resulting 32-kDa proBDNF moves, via the Golgi apparatus, into the trans-Golgi network (TGN) where two kinds of secretory vesicles are generated: those of the constitutive secretory pathway and those of the regulated pathway, whose secretion is activity-dependent. ProBDNF packaged in both types of vesicles is either proteolytically cleaved and secreted as 14-kDa mBDNF, or secreted as proBDNF and cleaved by extracellular proteases. The extent of the intra and extracellular processing of proBDNF is not exactly clear, but secretion of the proBDNF predominates. Both proBDNF and mBDNF are preferentially packaged into vesicles of the regulated secretory pathway. Once released, proBDNF binds preferentially to pan neurotrophin receptor p75NTR and mBDNF binds preferentially to both pre-and post-synaptic TrkB receptors, activating different intracellular secondary messenger cascades and affecting distinct cellular responses.
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Figure 2: BDNF processing, packaging and secretion in neurons. BDNF is synthesized as a pre-proBDNF protein, which has its pre-sequence cleaved off in the endoplasmic reticulum (ER). The resulting 32-kDa proBDNF moves, via the Golgi apparatus, into the trans-Golgi network (TGN) where two kinds of secretory vesicles are generated: those of the constitutive secretory pathway and those of the regulated pathway, whose secretion is activity-dependent. ProBDNF packaged in both types of vesicles is either proteolytically cleaved and secreted as 14-kDa mBDNF, or secreted as proBDNF and cleaved by extracellular proteases. The extent of the intra and extracellular processing of proBDNF is not exactly clear, but secretion of the proBDNF predominates. Both proBDNF and mBDNF are preferentially packaged into vesicles of the regulated secretory pathway. Once released, proBDNF binds preferentially to pan neurotrophin receptor p75NTR and mBDNF binds preferentially to both pre-and post-synaptic TrkB receptors, activating different intracellular secondary messenger cascades and affecting distinct cellular responses.

Mentions: BDNF protein is synthesized as a precursor, pre-proBDNF protein, resulting after cleavage in a 32-kDa proBDNF protein. ProBDNF is either proteolytically cleaved intracellularly by enzymes like furin or pro-convertases and secreted as the 14‚ÄČkDa mature BDNF (mBDNF), or secreted as proBDNF and then cleaved by extracellular proteases, such as metalloproteinases and plasmin, to mBDNF (reviewed in Lessmann et al., 2003). The extent of intracellular and extracellular processing of proBDNF is not exactly clear, but proBDNF is less efficiently processed by intracellular proteases compared to other neurotrophins and secretion of proBDNF with respect to mBDNF seems to prevail (Mowla et al., 2001). Nevertheless, both proBDNF and mBDNF are preferentially sorted and packaged into vesicles of the activity-regulated secretory pathway. ProBDNF is not an inactive precursor of BDNF, but rather it is a signalling protein in its own right (see below). ProBDNF is released in the immature and mature CNS in an activity dependent manner (Mowla et al., 2001; Yang et al., 2009; Figure 2). The intracellular localization of BDNF is predominantly somatodendritic but it is also enriched in the dendrites, where it is also synthesized from mRNA in close proximity to spines (reviewed in Tongiorgi et al., 1997; Tongiorgi, 2008). BDNF is present in pre- and postsynaptic compartments and it can undergo both retrograde and anterograde transport. Moreover, BDNF can act via autocrine and paracrine mechanisms, depending on the site of cell surface receptors through which it signals (reviewed in Murer et al., 2001). The activity-regulated release of BDNF can occur via three mechanisms dependent on the site of release: (i) Ca2+ influx-dependent release from postsynaptic sites, which is mediated by Ca2+ influx through ionotropic glutamate receptors and voltage gated Ca2+-channels (Hartmann et al., 2001), (ii) Ca2+ influx- dependent release from presynaptic sites (Balkowiec and Katz, 2002), and (iii) Ca2+ influx-independent release that relies on Ca2+ release from intracellular stores (Griesbeck et al., 1999). Neuronal activity also regulates the transport of BDNF mRNA and protein into dendrites (reviewed in Tongiorgi et al., 1997; Tongiorgi, 2008), and these mechanisms are considered to be responsible for the ability of locally translated BDNF to modulate synaptic transmission and synaptogenesis (reviewed in Lu and Figurov, 1997). Evidence of the importance for the regulated trafficking of BDNF to cognitive function comes from the only single nucleotide polymorphism (SNP) identified in the human BDNF gene, Val66Met (Egan et al., 2003). This SNP consists in the substitution of Met for Val at position 66 in the pro-region of BDNF which not only alters the trafficking, distribution and activity-dependent release of BDNF from neurons but also results in memory impairments in rodent models and in an increased susceptibility towards disorders such as depression, bipolar disorder and eating disorder in humans carrying the mutation (Chen et al., 2004).


A simple role for BDNF in learning and memory?

Cunha C, Brambilla R, Thomas KL - Front Mol Neurosci (2010)

BDNF processing, packaging and secretion in neurons. BDNF is synthesized as a pre-proBDNF protein, which has its pre-sequence cleaved off in the endoplasmic reticulum (ER). The resulting 32-kDa proBDNF moves, via the Golgi apparatus, into the trans-Golgi network (TGN) where two kinds of secretory vesicles are generated: those of the constitutive secretory pathway and those of the regulated pathway, whose secretion is activity-dependent. ProBDNF packaged in both types of vesicles is either proteolytically cleaved and secreted as 14-kDa mBDNF, or secreted as proBDNF and cleaved by extracellular proteases. The extent of the intra and extracellular processing of proBDNF is not exactly clear, but secretion of the proBDNF predominates. Both proBDNF and mBDNF are preferentially packaged into vesicles of the regulated secretory pathway. Once released, proBDNF binds preferentially to pan neurotrophin receptor p75NTR and mBDNF binds preferentially to both pre-and post-synaptic TrkB receptors, activating different intracellular secondary messenger cascades and affecting distinct cellular responses.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2821174&req=5

Figure 2: BDNF processing, packaging and secretion in neurons. BDNF is synthesized as a pre-proBDNF protein, which has its pre-sequence cleaved off in the endoplasmic reticulum (ER). The resulting 32-kDa proBDNF moves, via the Golgi apparatus, into the trans-Golgi network (TGN) where two kinds of secretory vesicles are generated: those of the constitutive secretory pathway and those of the regulated pathway, whose secretion is activity-dependent. ProBDNF packaged in both types of vesicles is either proteolytically cleaved and secreted as 14-kDa mBDNF, or secreted as proBDNF and cleaved by extracellular proteases. The extent of the intra and extracellular processing of proBDNF is not exactly clear, but secretion of the proBDNF predominates. Both proBDNF and mBDNF are preferentially packaged into vesicles of the regulated secretory pathway. Once released, proBDNF binds preferentially to pan neurotrophin receptor p75NTR and mBDNF binds preferentially to both pre-and post-synaptic TrkB receptors, activating different intracellular secondary messenger cascades and affecting distinct cellular responses.
Mentions: BDNF protein is synthesized as a precursor, pre-proBDNF protein, resulting after cleavage in a 32-kDa proBDNF protein. ProBDNF is either proteolytically cleaved intracellularly by enzymes like furin or pro-convertases and secreted as the 14‚ÄČkDa mature BDNF (mBDNF), or secreted as proBDNF and then cleaved by extracellular proteases, such as metalloproteinases and plasmin, to mBDNF (reviewed in Lessmann et al., 2003). The extent of intracellular and extracellular processing of proBDNF is not exactly clear, but proBDNF is less efficiently processed by intracellular proteases compared to other neurotrophins and secretion of proBDNF with respect to mBDNF seems to prevail (Mowla et al., 2001). Nevertheless, both proBDNF and mBDNF are preferentially sorted and packaged into vesicles of the activity-regulated secretory pathway. ProBDNF is not an inactive precursor of BDNF, but rather it is a signalling protein in its own right (see below). ProBDNF is released in the immature and mature CNS in an activity dependent manner (Mowla et al., 2001; Yang et al., 2009; Figure 2). The intracellular localization of BDNF is predominantly somatodendritic but it is also enriched in the dendrites, where it is also synthesized from mRNA in close proximity to spines (reviewed in Tongiorgi et al., 1997; Tongiorgi, 2008). BDNF is present in pre- and postsynaptic compartments and it can undergo both retrograde and anterograde transport. Moreover, BDNF can act via autocrine and paracrine mechanisms, depending on the site of cell surface receptors through which it signals (reviewed in Murer et al., 2001). The activity-regulated release of BDNF can occur via three mechanisms dependent on the site of release: (i) Ca2+ influx-dependent release from postsynaptic sites, which is mediated by Ca2+ influx through ionotropic glutamate receptors and voltage gated Ca2+-channels (Hartmann et al., 2001), (ii) Ca2+ influx- dependent release from presynaptic sites (Balkowiec and Katz, 2002), and (iii) Ca2+ influx-independent release that relies on Ca2+ release from intracellular stores (Griesbeck et al., 1999). Neuronal activity also regulates the transport of BDNF mRNA and protein into dendrites (reviewed in Tongiorgi et al., 1997; Tongiorgi, 2008), and these mechanisms are considered to be responsible for the ability of locally translated BDNF to modulate synaptic transmission and synaptogenesis (reviewed in Lu and Figurov, 1997). Evidence of the importance for the regulated trafficking of BDNF to cognitive function comes from the only single nucleotide polymorphism (SNP) identified in the human BDNF gene, Val66Met (Egan et al., 2003). This SNP consists in the substitution of Met for Val at position 66 in the pro-region of BDNF which not only alters the trafficking, distribution and activity-dependent release of BDNF from neurons but also results in memory impairments in rodent models and in an increased susceptibility towards disorders such as depression, bipolar disorder and eating disorder in humans carrying the mutation (Chen et al., 2004).

Bottom Line: More recently, BDNF has also emerged as an important regulator of synaptogenesis and synaptic plasticity mechanisms underlying learning and memory in the adult CNS.We will show that maturation of BDNF, its cellular localization and its ability to regulate both excitatory and inhibitory synapses in the CNS may result in conflicting alterations in synaptic plasticity and memory formation.Lack of a precise knowledge about the mechanisms by which BDNF influences higher cognitive functions and complex behaviours may constitute a severe limitation in the possibility to devise BDNF-based therapeutics for human disorders of the CNS.

View Article: PubMed Central - PubMed

Affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca Milan, Italy.

ABSTRACT
Since its discovery almost three decades ago, the secreted neurotrophin brain-derived neurotrophic factor (BDNF) has been firmly implicated in the differentiation and survival of neurons of the CNS. More recently, BDNF has also emerged as an important regulator of synaptogenesis and synaptic plasticity mechanisms underlying learning and memory in the adult CNS. In this review we will discuss our knowledge about the multiple intracellular signalling pathways activated by BDNF, and the role of this neurotrophin in long-term synaptic plasticity and memory formation as well as in synaptogenesis. We will show that maturation of BDNF, its cellular localization and its ability to regulate both excitatory and inhibitory synapses in the CNS may result in conflicting alterations in synaptic plasticity and memory formation. Lack of a precise knowledge about the mechanisms by which BDNF influences higher cognitive functions and complex behaviours may constitute a severe limitation in the possibility to devise BDNF-based therapeutics for human disorders of the CNS.

No MeSH data available.


Related in: MedlinePlus