Choline Transporter 1 Maintains Cholinergic Function in Choline Acetyltransferase Haploinsufficiency
Open Access
- 16 June 2004
- journal article
- research article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 24 (24), 5459-5466
- https://doi.org/10.1523/jneurosci.1106-04.2004
Abstract
Choline acetyltransferase (ChAT), the enzyme that synthesizes the neurotransmitter acetylcholine (ACh), is thought to be present in kinetic excess in cholinergic neurons. The rate-limiting factor in ACh production is the provision of choline to ChAT. Cholinergic neurons are relatively unique in their expression of the choline transporter 1 (CHT1), which exhibits high-affinity for choline and catalyzes its uptake from the extracellular space to the neuron. Multiple lines of evidence indicate that the activity of CHT1 is a key determinant of choline supply for ACh synthesis. We examined the interaction of ChAT and ChT activity using mice heterozygous for a null mutation in theChatgene (Chat+/-). In these mice, brain ChAT activity was reduced by 40-50% relative to the wild type, but brain ACh levels as well as ACh content and depolarization-evoked ACh release in hippocampal slices were normal. However, the amount of choline taken up by CHT1 and ACh synthesizedde novofrom choline transported by CHT1 in hippocampal slices, as well as levels of CHT1 mRNA in the septum and CHT1 protein in several regions of the CNS, were 50-100% higher inChat+/- than inChat+/+ mice. Thus, haploinsufficiency of ChAT leads to an increased expression of CHT1. Increased ChT activity may compensate for the reduced ChAT activity inChat+/- mice, contributing to the maintenance of apparently normal cholinergic function as reflected by normal performance of these mice in several behavioral assays.This publication has 45 references indexed in Scilit:
- Changes in cortical acetyl‐CoA metabolism after selective basal forebrain cholinergic degeneration by 192IgG‐saporinJournal of Neurochemistry, 2003
- Distribution of high affinity choline transporter immunoreactivity in the primate central nervous systemJournal of Comparative Neurology, 2003
- Single Nucleotide Polymorphism of the Human High Affinity Choline Transporter Alters Transport RateOnline Journal of Public Health Informatics, 2002
- Functional Characterization of Phosphorylation of 69-kDa Human Choline Acetyltransferase at Serine 440 by Protein Kinase COnline Journal of Public Health Informatics, 2001
- Molecular Cloning of a Human, Hemicholinium-3-Sensitive Choline TransporterBiochemical and Biophysical Research Communications, 2000
- Expression, purification and characterization of recombinant human choline acetyltransferase: phosphorylation of the enzyme regulates catalytic activityBiochemical Journal, 2000
- In vivo synthesis of phosphatidylcholine in rat brain via the phospholipid methylation pathwayBrain Research, 1987
- 4‐(1‐Naphthylvinyl)pyridine Decreases Brain Acetylcholine In Vivo, but Does Not Alter the Level of Acetyl‐CoAJournal of Neurochemistry, 1986
- High affinity choline uptake in striatum and hippocampus: Differential effects of treatments which release acetylcholineLife Sciences, 1978
- NOREPINEPHRINE METABOLISM IN THE CENTRAL NERVOUS SYSTEM OF MAN: STUDIES USING 3‐METHOXY‐4‐HYDROXYPHENYLETHYLENE GLYCOL LEVELS IN CEREBROSPINAL FLUIDJournal of Neurochemistry, 1973