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Choline transporters, cholinergic transmission and cognition

Nature Reviews Neuroscience volume 6, pages 48–56 (2005)Cite this article

Key Points

  • The transport of choline into neuronal terminals through the high-affinity choline uptake transporter (CHT) is essential for cholinergic transmission. Forebrain cholinergic systems have been shown to mediate attentional functions and capacities. This article reviews recent research that highlighted the role of CHT function in cognitive abilities and showed that the capacity of the CHT to transport choline is regulated in part by intracellular trafficking of CHTs. Furthermore, alterations in CHT capacity are hypothesized to contribute to the manifestation of cognitive disorders.

  • Presynaptic cholinergic activity has long been known to be an important factor that contributes to the regulation of CHT capacity. However, accumulating evidence indicates that multiple signalling mechanisms regulate CHT function. These mechanisms might be used by cholinergic as well as non-cholinergic systems to influence the capacity of the CHT. The regulation of the trafficking of CHTs from vesicular to plasma membrane probably represents such a mechanism.

  • Evidence from mice with mutations of genes that encode CHT, choline acetyltransferase or acetylcholinesterase indicates that the capacity of CHTs can compensate for abnormalities in cholinergic transmission. However, the mechanisms that underlie such plasticity of CHT function are largely unknown. Understanding the post-translational regulation of CHTs represents a vital subject of research designed to determine the role of cholinergic transmission in neurological and psychiatric disorders.

  • Recent experiments used a choline-sensitive micro-electrode to measure changes in extracellular choline concentrations amperometrically. These studies showed the feasibility of monitoring acetylcholine release at a high temporal resolution by measuring increases in extracellular choline generated by hydrolysis of acetylcholine. Furthermore, this method seems to allow the assessment of CHT capacity in vivo, because choline signals were shown to be rapidly cleared through hemicholinium-sensitive mechanisms.

  • Animal studies have shown that attentional performance is associated with increases in cortical acetylcholine efflux as well as an increased capacity of the CHT to import choline and with an increased translocation of CHTs to plasma membranes. These studies begin to unravel the role of the CHT in controlling cholinergic transmission during cognitive, and particularly attentional, challenges.

  • The evidence that links abnormalities in the regulation of CHT function with the manifestation of cognitive impairments in neurodegenerative and neuropsychiatric disorders is discussed. If impaired CHT regulation indeed represents a causal variable in the decline of cholinergic function and cognitive abilities in these disorders, then conventional approaches to enhance presynaptic cholinergic activity might be of limited use. Alternatively, new approaches to directly stimulate the capacity of CHT might represent a promising strategy for the treatment of such cognitive symptoms.

Abstract

Cholinergic projections to the cortex and hippocampus mediate fundamental cognitive processes. The capacity of the high-affinity choline uptake transporter (CHT) to import choline from the extracellular space to presynaptic terminals is essential for normal acetylcholine synthesis and therefore cholinergic transmission. The CHT is highly regulated, and the cellular mechanisms that modulate its capacity show considerable plasticity. Recent evidence links changes in CHT capacity with the ability to perform tasks that tax attentional processes and capacities. Abnormal regulation of CHT capacity might contribute to the cognitive impairments that are associated with neurodegenerative and neuropsychiatric disorders. Therefore, the CHT might represent a productive target for the development of new pharmacological treatments for these conditions.

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Figure 1: Schematic illustration of the main steps of presynaptic cholinergic transmission.
Figure 2: Amperometric recording of choline using enzyme-coated microelectrodes and evidence that choline signals reflect endogenous acetylcholine release.
Figure 3: Importance of cortical cholinergic transmission in attentional performance.

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Acknowledgements

The authors' research is funded by Public Health Service grants. We thank J. McGaughy (University of New Hampshire), V. Martinez (University of Michigan) and two anonymous reviewers for helpful comments on a draft of this manuscript.

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  1. Department of Psychology, University of Michigan, 4032 East Hall, 525 East University Avenue, Ann Arbor, 48109, Michigan, USA

    Martin Sarter & Vinay Parikh

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DATABASES

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AChE

ChAT

CHT

PAR4

VAChT

OMIM

Alzheimer's disease

schizophrenia

FURTHER INFORMATION

Encyclopedia of Life Sciences

Acetylcholine

Glossary

NEUROTRANSMITTER TRANSPORTERS

Proteins that primarily transport (or 'recycle') neurotransmitters or their metabolites from the extracellular space into presynaptic neurons.

K M

Measure of enzyme kinetics. Km indicates the substrate concentration at which the reaction rate is half its maximal value.

SINGLE NUCLEOTIDE POLYMORPHISM

Genetic variation within a person's DNA sequence. It occurs when a single nucleotide (for example, thymine) replaces one of the other three nucleotides (for example, cytosine).

MICRODIALYSIS

A perfused probe that consists of a semi-permeable membrane is placed into the extracellular space to collect proportions of an analyte over time.

AMPEROMETRY

A constant fixed potential is applied to an electrochemical device (such as a sensor or electrode), and the current response, which reflects oxidation or reduction of analytes of interest, is monitored.

V MAX

Measure of enzyme kinetics. Vmax indicates the maximum velocity of the formation of an enzyme–substrate complex.

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Sarter, M., Parikh, V. Choline transporters, cholinergic transmission and cognition. Nat Rev Neurosci 6, 48–56 (2005). https://doi.org/10.1038/nrn1588

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