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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 actions on ligand-gated, voltage-gated and second-messenger-gated ion channels, which mediate fast and slow synaptic transmission in neurons. BDNF is transported anterogradely and retrogradely and can activate TrkB receptors both pre- and postsynaptically. The association of BDNF with TrkB modulates or activates ion channels including Na+, Ca2+ and K+ channels, within a range of seconds to minutes, through intracellular signalling cascades. TRPC3 is a non-selective cation channel that needs to be phosphorylated by TrkB to open, via PLCγ, a process also acting in the range of minutes. BDNF enhances glutamatergic neurotransmission by increasing open probability of NMDA (by promoting its phosphorylation, via Fyn-dependent and Fyn-independent mechanisms) and by upregulating AMPA expression. ERK signalling is involved in both NMDA and AMPA gating. In the millisecond range, BDNF/TrkB can directly gate the Nav1.9 Na+, the Kv1.3 K+ and the Kir3 K+ ion channels. The resulting depolarizations contribute to the facilitation of the induction of LTP.
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Figure 4: BDNF/TrkB actions on ligand-gated, voltage-gated and second-messenger-gated ion channels, which mediate fast and slow synaptic transmission in neurons. BDNF is transported anterogradely and retrogradely and can activate TrkB receptors both pre- and postsynaptically. The association of BDNF with TrkB modulates or activates ion channels including Na+, Ca2+ and K+ channels, within a range of seconds to minutes, through intracellular signalling cascades. TRPC3 is a non-selective cation channel that needs to be phosphorylated by TrkB to open, via PLCγ, a process also acting in the range of minutes. BDNF enhances glutamatergic neurotransmission by increasing open probability of NMDA (by promoting its phosphorylation, via Fyn-dependent and Fyn-independent mechanisms) and by upregulating AMPA expression. ERK signalling is involved in both NMDA and AMPA gating. In the millisecond range, BDNF/TrkB can directly gate the Nav1.9 Na+, the Kv1.3 K+ and the Kir3 K+ ion channels. The resulting depolarizations contribute to the facilitation of the induction of LTP.

Mentions: BDNF elicits rapid effects on synaptic transmission and membrane excitability primarily via activation of these signalling pathways. BDNF affects synaptic transmission by acting at pre- and postsynaptic sites. It can induce the presynaptic release of glutamate and GABA through TrkB–ERK-mediated phosphorylation of synapsin (Jovanovic et al., 2000). At least for glutamatergic synapses, the BDNF-induced enhancement in transmission is mediated by an increase in the number of docked vesicles at the active zones of synapses (Tyler and Pozzo-Miller, 2001). Postsynaptically, BDNF also rapidly modulates excitatory and inhibitory transmission by altering the activation kinetics of glutamatergic NMDA receptors and inhibitory GABA receptors (reviewed in Rose et al., 2004). While the inhibition of GABA transmission in the adult brain occurs via TrkB–PLCγ signalling, the potentiation of NMDA receptor responses and enhancement in Ca2+ influx is meditated by a novel mechanism in which the src-family tyrosine kinase Fyn, activated by TrkB, directly phosphorylates the NR2B subunit. BDNF also upregulates surface expression of AMPA receptors by inducing their rapid surface translocation to increase excitatory transmission (Narisawa-Saito et al., 2002; Itami et al., 2003), an effect that requires ERK signalling (Li and Keifer, 2009; Figure 4).


A simple role for BDNF in learning and memory?

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

BDNF/TrkB actions on ligand-gated, voltage-gated and second-messenger-gated ion channels, which mediate fast and slow synaptic transmission in neurons. BDNF is transported anterogradely and retrogradely and can activate TrkB receptors both pre- and postsynaptically. The association of BDNF with TrkB modulates or activates ion channels including Na+, Ca2+ and K+ channels, within a range of seconds to minutes, through intracellular signalling cascades. TRPC3 is a non-selective cation channel that needs to be phosphorylated by TrkB to open, via PLCγ, a process also acting in the range of minutes. BDNF enhances glutamatergic neurotransmission by increasing open probability of NMDA (by promoting its phosphorylation, via Fyn-dependent and Fyn-independent mechanisms) and by upregulating AMPA expression. ERK signalling is involved in both NMDA and AMPA gating. In the millisecond range, BDNF/TrkB can directly gate the Nav1.9 Na+, the Kv1.3 K+ and the Kir3 K+ ion channels. The resulting depolarizations contribute to the facilitation of the induction of LTP.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: BDNF/TrkB actions on ligand-gated, voltage-gated and second-messenger-gated ion channels, which mediate fast and slow synaptic transmission in neurons. BDNF is transported anterogradely and retrogradely and can activate TrkB receptors both pre- and postsynaptically. The association of BDNF with TrkB modulates or activates ion channels including Na+, Ca2+ and K+ channels, within a range of seconds to minutes, through intracellular signalling cascades. TRPC3 is a non-selective cation channel that needs to be phosphorylated by TrkB to open, via PLCγ, a process also acting in the range of minutes. BDNF enhances glutamatergic neurotransmission by increasing open probability of NMDA (by promoting its phosphorylation, via Fyn-dependent and Fyn-independent mechanisms) and by upregulating AMPA expression. ERK signalling is involved in both NMDA and AMPA gating. In the millisecond range, BDNF/TrkB can directly gate the Nav1.9 Na+, the Kv1.3 K+ and the Kir3 K+ ion channels. The resulting depolarizations contribute to the facilitation of the induction of LTP.
Mentions: BDNF elicits rapid effects on synaptic transmission and membrane excitability primarily via activation of these signalling pathways. BDNF affects synaptic transmission by acting at pre- and postsynaptic sites. It can induce the presynaptic release of glutamate and GABA through TrkB–ERK-mediated phosphorylation of synapsin (Jovanovic et al., 2000). At least for glutamatergic synapses, the BDNF-induced enhancement in transmission is mediated by an increase in the number of docked vesicles at the active zones of synapses (Tyler and Pozzo-Miller, 2001). Postsynaptically, BDNF also rapidly modulates excitatory and inhibitory transmission by altering the activation kinetics of glutamatergic NMDA receptors and inhibitory GABA receptors (reviewed in Rose et al., 2004). While the inhibition of GABA transmission in the adult brain occurs via TrkB–PLCγ signalling, the potentiation of NMDA receptor responses and enhancement in Ca2+ influx is meditated by a novel mechanism in which the src-family tyrosine kinase Fyn, activated by TrkB, directly phosphorylates the NR2B subunit. BDNF also upregulates surface expression of AMPA receptors by inducing their rapid surface translocation to increase excitatory transmission (Narisawa-Saito et al., 2002; Itami et al., 2003), an effect that requires ERK signalling (Li and Keifer, 2009; Figure 4).

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