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TrkB signalling pathways in LTP and learning

Key Points

  • TrkB, a neurotrophin receptor tyrosine kinase well known for its functions during nervous system development, has recently emerged as a potent regulator of hippocampal long-term potentiation (LTP) and learning.

  • The signalling pathways that mediate the involvement of TrkB in hippocampal LTP have been dissected genetically. Analyses of mouse models in which a single phosphorylation site on the TrkB receptor was mutated have revealed that signalling through the phospholipase Cγ (PLCγ) site of TrkB, but not the Shc adaptor protein site, is important for both the early and the late phases of hippocampal LTP. Furthermore, point mutations at the PLCγ site impaired the Ca2+-dependent signalling pathway but not mitogen-activated protein kinase activation and nuclear translocation, implicating a novel pathway by which TrkB activates cyclic AMP-responsive element-binding protein (CREB) through the PLCγ site as being responsible for the hippocampal synaptic plasticity downstream of TrkB.

  • The PLCγ site-activated pathways of TrkB have also been shown to underlie both associative learning and LTP triggered at the CA3–CA1 synapse in conscious mice. These experiments are the first to investigate whether the molecular pathways required for learning are also those that generate LTP in a mouse while it is learning a task.

  • Most of the effects of TrkB on synaptic plasticity seem to occur through modulation of ion channel properties through crosstalk between TrkB-activated signalling (either by brain-derived neurotrophic factor or occurring in a neurotrophin-independent manner) and pathways that underlie plasticity at glutamatergic synapses.

  • Given the findings discussed here, the possibility of manipulating signalling downstream of TrkB to enhance learning should be explored.

Abstract

Understanding the mechanisms that underlie learning is one of the most fascinating and central aims of neurobiological research. Hippocampal long-term potentiation (LTP) is widely regarded as a prime candidate for the cellular mechanism of learning. The receptor tyrosine kinase TrkB (also known as NTRK2), known primarily for its function during PNS and CNS development, has emerged in recent years as a potent regulator of hippocampal LTP. Here I describe efforts to understand the signalling pathways and molecular mechanisms that underlie the involvement of TrkB in LTP and learning.

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Figure 1: Major TrkB-signalling-activated pathways.
Figure 2: Interactions between TrkB signalling and glutamate receptors.

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Acknowledgements

I thank members of the laboratory for helpful discussions and comments. This work was supported in part by grants from the European Union (EU FP6 MEMORIES, 037831; EU FP6 StemStroke, 037526).

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Glossary

Long-term potentiation

(LTP). A persistent increase in synaptic strength induced by brief high-frequency electrical stimulation of afferent fibres or coincident activation of pre- and postsynaptic neurons.

Synaptic plasticity

The ability of a synapse to change in strength.

Dendritic spike

An action potential generated in the dendrite of a neuron.

Long-term memory

(LTM). In contrast to short-term memory, LTM has a high capacity for storage of information for potentially unlimited duration.

Adaptor molecules

Molecules containing distinct modular domains, which typically mediate protein–protein interactions, allowing these proteins to form signal transduction complexes.

Phosphotyrosine-binding (PTB) domains

Modular domains within a protein structure. They usually bind to phosphorylated tyrosine residues and are often found in signal transduction proteins.

Src homology 2 (SH2) domains

Modular domains within a protein structure. They usually bind to phosphorylated tyrosine residues and are often found in signal transduction proteins.

Associative learning

Any learning process in which a new response becomes associated with a particular stimulus. In animal behaviour it has mainly been limited to learning that occurs through classical and instrumental conditioning.

Conditional mutagenesis

Regional and temporal control of gene inactivation in mice.

Hyperpolarization

A change in a cell's membrane potential that makes it more negative.

Pavlovian fear conditioning

(FC). A simple form of associative learning that is considered a model system in which to examine the neurobiological basis of learning and memory in the mammalian brain. In this learning paradigm an initially neutral conditioned stimulus (CS), such as a tone, elicits defensive responses on association with an aversive unconditioned stimulus (US), such as a mild electric footshock.

Trace eyeblink conditioning

A form of classical conditioning extensively used to study neural structures and mechanisms that underlie learning and memory. It is based on a relatively simple procedure that often consists of pairing an auditory (or visual) stimulus with an eyeblink-eliciting unconditioned stimulus (such as a mild puff of air to the cornea or a mild shock).

Synaptosome

A subcellular fraction obtained from homogenization of brain tissues that is rich in chemical synapses. Used in biochemical studies.

Open probability

The probability of an individual ion channel protein being in the open state under a given condition, observed as the fraction of the time that an ionic current is flowing. The value can be between zero and one.

Spatial memory formation

A type of learning that is dependent on an intact hippocampus. The primary method of studying spatial learning has been to put a rodent in a maze in which the rodent learns where a particular resource is and how to get to it from the starting location by developing a strategy based on a set of distal visual cues.

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Minichiello, L. TrkB signalling pathways in LTP and learning. Nat Rev Neurosci 10, 850–860 (2009). https://doi.org/10.1038/nrn2738

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