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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.


Model proposed for the role of BDNF on excitatory and inhibitory circuits in the brain and its consequences on LTP and LTM. While a physiological amount of BDNF in the normal brain has been demonstrated to have positive effects on learning and memory, both an increased level of BDNF, and a decreased level of BDNF may disrupt the equilibrium between inhibitory and excitatory neurotransmission in the brain, leading to a loss of synaptic refinement and consequently impairing LTP, learning and memory.
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Figure 5: Model proposed for the role of BDNF on excitatory and inhibitory circuits in the brain and its consequences on LTP and LTM. While a physiological amount of BDNF in the normal brain has been demonstrated to have positive effects on learning and memory, both an increased level of BDNF, and a decreased level of BDNF may disrupt the equilibrium between inhibitory and excitatory neurotransmission in the brain, leading to a loss of synaptic refinement and consequently impairing LTP, learning and memory.

Mentions: The development of transgenic mice particularly those overexpressing BDNF, has also added new and contradictory information concerning the relationship between BDNF, LTP and learning and memory. Mice overexpressing the full-length TrkB receptor have improved cognitive skills but attenuated LTP (Koponen et al., 2004), and mice overexpressing a truncated form of the TrkB receptor show a memory deficit in the MWM but normal LTP (Saarelainen et al., 2000). These studies indicate that the requirement for TrkB-mediated signalling in LTM and LTP are different. Transgenic mice overexpressing BDNF under the β-actin promoter presented a 30–40% increase in the level of BDNF protein in the brain and revealed a LTP disruption in the CA1 area and a significant memory deficit in the passive avoidance test (Croll et al., 1999). This corresponded roughly to the same effect of attenuating BDNF activity. Similarly, more restricted overexpression of BDNF (two- to threefold depending on the structure) to the postnatal forebrain resulted in learning and memory impairments in both passive avoidance, eight-arm radial maze and MWM (Cunha et al., 2009). These studies suggest that BDNF may negatively regulate learning and memory and that too much as well as too little BDNF can impair LTM and LTP. These observations in transgenic mice overexpressing BDNF may reflect a developmental shift in the balance between inhibitory and excitatory transmission in the brain. Indeed, mutant mice overexpressing BDNF in the forebrain show an acceleration in the maturation of GABAergic innervation and inhibition in the visual cortex (Huang et al., 1999). This idea is supported by evidence that heterozygous BDNF KO mice show several deficits in interneuron maturation, including the altered expression of hallmark calcium binding proteins and peptide neurotransmitters (Jones et al., 1994). However, a general role for BDNF in modulating inhibitory circuitry is unknown. We here propose a model for the role of BDNF in modulating excitatory and inhibitory transmission in the brain and its functional consequences in learning and memory (Figure 5).


A simple role for BDNF in learning and memory?

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

Model proposed for the role of BDNF on excitatory and inhibitory circuits in the brain and its consequences on LTP and LTM. While a physiological amount of BDNF in the normal brain has been demonstrated to have positive effects on learning and memory, both an increased level of BDNF, and a decreased level of BDNF may disrupt the equilibrium between inhibitory and excitatory neurotransmission in the brain, leading to a loss of synaptic refinement and consequently impairing LTP, learning and memory.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Model proposed for the role of BDNF on excitatory and inhibitory circuits in the brain and its consequences on LTP and LTM. While a physiological amount of BDNF in the normal brain has been demonstrated to have positive effects on learning and memory, both an increased level of BDNF, and a decreased level of BDNF may disrupt the equilibrium between inhibitory and excitatory neurotransmission in the brain, leading to a loss of synaptic refinement and consequently impairing LTP, learning and memory.
Mentions: The development of transgenic mice particularly those overexpressing BDNF, has also added new and contradictory information concerning the relationship between BDNF, LTP and learning and memory. Mice overexpressing the full-length TrkB receptor have improved cognitive skills but attenuated LTP (Koponen et al., 2004), and mice overexpressing a truncated form of the TrkB receptor show a memory deficit in the MWM but normal LTP (Saarelainen et al., 2000). These studies indicate that the requirement for TrkB-mediated signalling in LTM and LTP are different. Transgenic mice overexpressing BDNF under the β-actin promoter presented a 30–40% increase in the level of BDNF protein in the brain and revealed a LTP disruption in the CA1 area and a significant memory deficit in the passive avoidance test (Croll et al., 1999). This corresponded roughly to the same effect of attenuating BDNF activity. Similarly, more restricted overexpression of BDNF (two- to threefold depending on the structure) to the postnatal forebrain resulted in learning and memory impairments in both passive avoidance, eight-arm radial maze and MWM (Cunha et al., 2009). These studies suggest that BDNF may negatively regulate learning and memory and that too much as well as too little BDNF can impair LTM and LTP. These observations in transgenic mice overexpressing BDNF may reflect a developmental shift in the balance between inhibitory and excitatory transmission in the brain. Indeed, mutant mice overexpressing BDNF in the forebrain show an acceleration in the maturation of GABAergic innervation and inhibition in the visual cortex (Huang et al., 1999). This idea is supported by evidence that heterozygous BDNF KO mice show several deficits in interneuron maturation, including the altered expression of hallmark calcium binding proteins and peptide neurotransmitters (Jones et al., 1994). However, a general role for BDNF in modulating inhibitory circuitry is unknown. We here propose a model for the role of BDNF in modulating excitatory and inhibitory transmission in the brain and its functional consequences in learning and memory (Figure 5).

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.