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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–TrkB and BDNF–p75NTR signalling pathways. BDNF binds TrkB with high affinity to induce its dimerization and autophosphorylation of tyrosine residues in the cytoplasmic kinase domain that serve as docking sites for effector molecules and trigger the activation of three main signalling pathways: PLCγ, PI3K and ERK cascades, which ultimately lead to the phosphorylation and activation of the transcription factor CREB that mediates transcription of genes essential for the survival and differentiation of neurons. The recruitment of PLCγ increases intracellular Ca2+ levels and leads to the activation of CaMKII to phosphorylate CREB. PI3K can be activated via the Shc/Grb2/SOS complex through Gab1 and by IRS1/2. Lipid products generated by the activated PI3K, the phosphatidylinositides, bind and activate protein kinase Akt, upstream of CREB. The ERK cascade can be activated both by the Shc/Grb2/SOS complex and by PI3K. ERK phosphorylation leads directly to CREB phosphorylation. Both Akt and ERK activate mTOR, responsible for enhanced translation initiation. BDNF binds p75NTR with low affinity, leading to apoptosis through the JNK cascade or cell survival through the NF-kB cascade. PLCγ, phospholipase Cγ; PI3K, phosphatidylinositol 3-kinase; ERK, extracellular signal-regulated kinase; CaMKII, calcium-calmodulin dependent kinase; Shc, src homology domain containing; Grb2, growth factor receptor-bound protein 2; SOS, son of sevenless; Gab1, Grb-associated binder 1; IRS1/2, insulin receptor substrates 1/2; CREB, cAMP-calcium response element binding protein; Ras, GTP binding protein; Raf, Ras associated factor; MEK, MAP/Erk kinase; mTOR, mammalian target of rapamycin; TRAF4/6, tumour necrosis factor receptor associated factor 4/6; RIP2, receptor interacting protein 2; JNK, c-Jun N-terminal kinase; NF-kB, nuclear factor k B.
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Figure 3: BDNF–TrkB and BDNF–p75NTR signalling pathways. BDNF binds TrkB with high affinity to induce its dimerization and autophosphorylation of tyrosine residues in the cytoplasmic kinase domain that serve as docking sites for effector molecules and trigger the activation of three main signalling pathways: PLCγ, PI3K and ERK cascades, which ultimately lead to the phosphorylation and activation of the transcription factor CREB that mediates transcription of genes essential for the survival and differentiation of neurons. The recruitment of PLCγ increases intracellular Ca2+ levels and leads to the activation of CaMKII to phosphorylate CREB. PI3K can be activated via the Shc/Grb2/SOS complex through Gab1 and by IRS1/2. Lipid products generated by the activated PI3K, the phosphatidylinositides, bind and activate protein kinase Akt, upstream of CREB. The ERK cascade can be activated both by the Shc/Grb2/SOS complex and by PI3K. ERK phosphorylation leads directly to CREB phosphorylation. Both Akt and ERK activate mTOR, responsible for enhanced translation initiation. BDNF binds p75NTR with low affinity, leading to apoptosis through the JNK cascade or cell survival through the NF-kB cascade. PLCγ, phospholipase Cγ; PI3K, phosphatidylinositol 3-kinase; ERK, extracellular signal-regulated kinase; CaMKII, calcium-calmodulin dependent kinase; Shc, src homology domain containing; Grb2, growth factor receptor-bound protein 2; SOS, son of sevenless; Gab1, Grb-associated binder 1; IRS1/2, insulin receptor substrates 1/2; CREB, cAMP-calcium response element binding protein; Ras, GTP binding protein; Raf, Ras associated factor; MEK, MAP/Erk kinase; mTOR, mammalian target of rapamycin; TRAF4/6, tumour necrosis factor receptor associated factor 4/6; RIP2, receptor interacting protein 2; JNK, c-Jun N-terminal kinase; NF-kB, nuclear factor k B.

Mentions: BDNF binds and activates, both pre- and postsynaptically, two different transmembrane receptor proteins: the tropomyosin related kinase TrkB receptor with high affinity, and the pan neurotrophin receptor p75NTR with low affinity (see Figure 3). At present, virtually all the synaptic effects of BDNF are attributed to TrkB activation. However, there is evidence that proBDNF binds p75NTR preferentially (Teng et al., 2005), which has distinct functional consequences (see below). BDNF can also bind TrkB splice variants lacking the tyrosine kinase domain required for downstream signalling, which are found mainly, but not exclusively, in glial cells (Klein et al., 1990). Therefore, the binding of BDNF to these TrkB variant receptors can act as a dominant-negative inhibitor of BDNF signalling by forming heterodimers with the full-length TrkB, and by internalizing BDNF to function as a clearance receptor (Haapasalo et al., 2002). ProBDNF, p75NTR and truncated TrkB isoforms can therefore be considered as negative regulatory mechanisms of the canonical BDNF–TrkB association, with consequent effects for synaptic plasticity and perhaps learning and memory.


A simple role for BDNF in learning and memory?

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

BDNF–TrkB and BDNF–p75NTR signalling pathways. BDNF binds TrkB with high affinity to induce its dimerization and autophosphorylation of tyrosine residues in the cytoplasmic kinase domain that serve as docking sites for effector molecules and trigger the activation of three main signalling pathways: PLCγ, PI3K and ERK cascades, which ultimately lead to the phosphorylation and activation of the transcription factor CREB that mediates transcription of genes essential for the survival and differentiation of neurons. The recruitment of PLCγ increases intracellular Ca2+ levels and leads to the activation of CaMKII to phosphorylate CREB. PI3K can be activated via the Shc/Grb2/SOS complex through Gab1 and by IRS1/2. Lipid products generated by the activated PI3K, the phosphatidylinositides, bind and activate protein kinase Akt, upstream of CREB. The ERK cascade can be activated both by the Shc/Grb2/SOS complex and by PI3K. ERK phosphorylation leads directly to CREB phosphorylation. Both Akt and ERK activate mTOR, responsible for enhanced translation initiation. BDNF binds p75NTR with low affinity, leading to apoptosis through the JNK cascade or cell survival through the NF-kB cascade. PLCγ, phospholipase Cγ; PI3K, phosphatidylinositol 3-kinase; ERK, extracellular signal-regulated kinase; CaMKII, calcium-calmodulin dependent kinase; Shc, src homology domain containing; Grb2, growth factor receptor-bound protein 2; SOS, son of sevenless; Gab1, Grb-associated binder 1; IRS1/2, insulin receptor substrates 1/2; CREB, cAMP-calcium response element binding protein; Ras, GTP binding protein; Raf, Ras associated factor; MEK, MAP/Erk kinase; mTOR, mammalian target of rapamycin; TRAF4/6, tumour necrosis factor receptor associated factor 4/6; RIP2, receptor interacting protein 2; JNK, c-Jun N-terminal kinase; NF-kB, nuclear factor k B.
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Figure 3: BDNF–TrkB and BDNF–p75NTR signalling pathways. BDNF binds TrkB with high affinity to induce its dimerization and autophosphorylation of tyrosine residues in the cytoplasmic kinase domain that serve as docking sites for effector molecules and trigger the activation of three main signalling pathways: PLCγ, PI3K and ERK cascades, which ultimately lead to the phosphorylation and activation of the transcription factor CREB that mediates transcription of genes essential for the survival and differentiation of neurons. The recruitment of PLCγ increases intracellular Ca2+ levels and leads to the activation of CaMKII to phosphorylate CREB. PI3K can be activated via the Shc/Grb2/SOS complex through Gab1 and by IRS1/2. Lipid products generated by the activated PI3K, the phosphatidylinositides, bind and activate protein kinase Akt, upstream of CREB. The ERK cascade can be activated both by the Shc/Grb2/SOS complex and by PI3K. ERK phosphorylation leads directly to CREB phosphorylation. Both Akt and ERK activate mTOR, responsible for enhanced translation initiation. BDNF binds p75NTR with low affinity, leading to apoptosis through the JNK cascade or cell survival through the NF-kB cascade. PLCγ, phospholipase Cγ; PI3K, phosphatidylinositol 3-kinase; ERK, extracellular signal-regulated kinase; CaMKII, calcium-calmodulin dependent kinase; Shc, src homology domain containing; Grb2, growth factor receptor-bound protein 2; SOS, son of sevenless; Gab1, Grb-associated binder 1; IRS1/2, insulin receptor substrates 1/2; CREB, cAMP-calcium response element binding protein; Ras, GTP binding protein; Raf, Ras associated factor; MEK, MAP/Erk kinase; mTOR, mammalian target of rapamycin; TRAF4/6, tumour necrosis factor receptor associated factor 4/6; RIP2, receptor interacting protein 2; JNK, c-Jun N-terminal kinase; NF-kB, nuclear factor k B.
Mentions: BDNF binds and activates, both pre- and postsynaptically, two different transmembrane receptor proteins: the tropomyosin related kinase TrkB receptor with high affinity, and the pan neurotrophin receptor p75NTR with low affinity (see Figure 3). At present, virtually all the synaptic effects of BDNF are attributed to TrkB activation. However, there is evidence that proBDNF binds p75NTR preferentially (Teng et al., 2005), which has distinct functional consequences (see below). BDNF can also bind TrkB splice variants lacking the tyrosine kinase domain required for downstream signalling, which are found mainly, but not exclusively, in glial cells (Klein et al., 1990). Therefore, the binding of BDNF to these TrkB variant receptors can act as a dominant-negative inhibitor of BDNF signalling by forming heterodimers with the full-length TrkB, and by internalizing BDNF to function as a clearance receptor (Haapasalo et al., 2002). ProBDNF, p75NTR and truncated TrkB isoforms can therefore be considered as negative regulatory mechanisms of the canonical BDNF–TrkB association, with consequent effects for synaptic plasticity and perhaps learning and memory.

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