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Reduced expression and capacity of the striatal high-affinity choline transporter in hyperdopaminergic mice

Authors :
Jerry B. Richards
Martin Sarter
Subbu Apparsundaram
Vinay Parikh
Rouba Kozak
Source :
Neuroscience. 141:379-389
Publication Year :
2006
Publisher :
Elsevier BV, 2006.

Abstract

Behavioral and neuronal abnormalities observed in mice exhibiting a reduced expression of the dopamine transporter model important aspects of schizophrenia, addiction, and attentional disorders. As the consequences of a chronic hyperdopaminergic tone for striatal output regulation have remained poorly understood, the present experiments were designed to determine the status of striatal interneuronal cholinergic neurotransmission in dopamine transporter knockdown animals. The high-affinity choline transporter represents the rate-limiting step of acetylcholine synthesis and release. Compared with wild type mice, striatal high-affinity choline transporter expression in dopamine transporter knockdown mice was significantly decreased. As in vivo basal striatal acetylcholine release did not differ between the strains, reduced high-affinity choline transporter expression in dopamine transporter knockdown mice was not due to reduced basal cholinergic activity. Furthermore, the proportion of high-affinity choline transporters expressed in plasma membrane-enriched versus vesicular membrane-enriched fractions did not differ from wild type animals, suggesting that changes in intracellular high-affinity choline transporter trafficking were not associated with lower overall levels of striatal high-affinity choline transporters. Synaptosomal choline uptake assays indicated a reduced capacity of striatal high-affinity choline transporters in dopamine transporter knockdown mice, and thus the functional significance of the reduced level of high-affinity choline transporter expression. Likewise, in vivo measures of the capacity of striatal high-affinity choline transporters to clear increases in extracellular choline concentrations, using choline-sensitive microelectrodes, revealed a 37-41% reduction in hemicholinium-sensitive clearance of exogenous choline in dopamine transporter knockdown mice. Furthermore, clearance of potassium-evoked choline signals was reduced in dopamine transporter knockdown mice (1.63+/-0.15 microM/s) compared with wild type animals (2.29+/-0.21 microM/s). Dysregulated striatal cholinergic neurotransmission is hypothesized to disrupt the integration of thalamic and cortical information at spiny projection neurons and thus to contribute to abnormal striatal information processing in dopamine transporter knockdown mice.

Details

ISSN :
03064522
Volume :
141
Database :
OpenAIRE
Journal :
Neuroscience
Accession number :
edsair.doi.dedup.....ff69e6004a981924741a75d32b64bf77
Full Text :
https://doi.org/10.1016/j.neuroscience.2006.03.055