Guzman MS, De Jaeger X, Raulic S, Souza IA, Li AX, Schmid S et al. Elimination of the vesicular acetylcholine transporter in the striatum reveals regulation of behaviour by cholinergic-glutamatergic co-transmission. PLoS Biol 9: e1001194

Molecular Brain Research Group, Robarts Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
PLoS Biology (Impact Factor: 9.34). 11/2011; 9(11):e1001194. DOI: 10.1371/journal.pbio.1001194
Source: PubMed


Cholinergic neurons in the striatum are thought to play major regulatory functions in motor behaviour and reward. These neurons express two vesicular transporters that can load either acetylcholine or glutamate into synaptic vesicles. Consequently cholinergic neurons can release both neurotransmitters, making it difficult to discern their individual contributions for the regulation of striatal functions. Here we have dissected the specific roles of acetylcholine release for striatal-dependent behaviour in mice by selective elimination of the vesicular acetylcholine transporter (VAChT) from striatal cholinergic neurons. Analysis of several behavioural parameters indicates that elimination of VAChT had only marginal consequences in striatum-related tasks and did not affect spontaneous locomotion, cocaine-induced hyperactivity, or its reward properties. However, dopaminergic sensitivity of medium spiny neurons (MSN) and the behavioural outputs in response to direct dopaminergic agonists were enhanced, likely due to increased expression/function of dopamine receptors in the striatum. These observations indicate that previous functions attributed to striatal cholinergic neurons in spontaneous locomotor activity and in the rewarding responses to cocaine are mediated by glutamate and not by acetylcholine release. Our experiments demonstrate how one population of neurons can use two distinct neurotransmitters to differentially regulate a given circuitry. The data also raise the possibility of using VAChT as a target to boost dopaminergic function and decrease high striatal cholinergic activity, common neurochemical alterations in individuals affected with Parkinson's disease.

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    • "We suggest that quantal ACh content and reduced VAChT protein levels or activity are important to define the morphology and distribution of SVs and the recycling of the RRP. Our results also suggest that functional alterations caused by VAChT deficiency [9], [55], [56] may involve multiple mechanisms, including a decreased in neurotransmitter storage in addition to deficits in the recycling and mobilization of the RRP. Future studies will be needed to clarify the relation between expression of VAChT and regulation of SVs mobility in neuromuscular synapses. "
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    ABSTRACT: In vertebrates, nerve muscle communication is mediated by the release of the neurotransmitter acetylcholine packed inside synaptic vesicles by a specific vesicular acetylcholine transporter (VAChT). Here we used a mouse model (VAChT KD(HOM)) with 70% reduction in the expression of VAChT to investigate the morphological and functional consequences of a decreased acetylcholine uptake and release in neuromuscular synapses. Upon hypertonic stimulation, VAChT KD(HOM) mice presented a reduction in the amplitude and frequency of miniature endplate potentials, FM 1-43 staining intensity, total number of synaptic vesicles and altered distribution of vesicles within the synaptic terminal. In contrast, under electrical stimulation or no stimulation, VAChT KD(HOM) neuromuscular junctions did not differ from WT on total number of vesicles but showed altered distribution. Additionally, motor nerve terminals in VAChT KD(HOM) exhibited small and flattened synaptic vesicles similar to that observed in WT mice treated with vesamicol that blocks acetylcholine uptake. Based on these results, we propose that decreased VAChT levels affect synaptic vesicle biogenesis and distribution whereas a lower ACh content affects vesicles shape.
    PLoS ONE 11/2013; 8(11):e78342. DOI:10.1371/journal.pone.0078342 · 3.23 Impact Factor
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    • "The central cholinergic system belongs to one of the firstly appearing transmitter system in the brain and has been involved in important functions of central nervous system (CNS) such as cognitive processes [1], motor coordination [2], attention, circadian rhythms [3], food reinforcement and drug addiction [4] and synaptic plasticity [5]. "
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    ABSTRACT: Acetylcholinesterase (AChE) is a key enzyme in termination of fast cholinergic transmission. In brain, acetylcholine (ACh) is produced by cholinergic neurons and released in extracellular space where it is cleaved by AChE anchored by protein PRiMA. Recently, we showed that the lack of AChE in brain of PRiMA knock-out (KO) mouse increased ACh levels 200–300 times. The PRiMA KO mice adapt nearly completely by the reduction of muscarinic receptor (MR) density. Here we investigated changes in MR density, AChE, butyrylcholinesterase (BChE) activity in brain in order to determine developmental period responsible for such adaptation. Brains were studied at embryonal day 18.5 and postnatal days (pd) 0, 9, 30, 120, and 425. We found that the AChE activity in PRiMA KO mice remained very low at all studied ages while in wild type (WT) mice it gradually increased till pd120. BChE activity in WT mice gradually decreased until pd9 and then increased by pd120, it continually decreased in KO mice till pd30 and remained unchanged thereafter. MR number increased in WT mice till pd120 and then became stable. Similarly, MR increased in PRiMA KO mice till pd30 and then remained stable, but the maximal level reached is approximately 50% of WT mice. Therefore, we provide the evidence that adaptive changes in MR happen up to pd30. This is new phenomenon that could contribute to the explanation of survival and nearly unchanged phenotype of PRiMA KO mice.
    PLoS ONE 07/2013; 8(7-7):e68265. DOI:10.1371/journal.pone.0068265 · 3.23 Impact Factor
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    • "Here, we found that VAChT overexpression is maintained at 6 months of age, spanning the age of animals used in this study. In contrast, no significant differences were found for ChAT and CHT protein expression, consistent with our and other's previous findings that alteration in VAChT does not affect other presynaptic cholinergic proteins (Guzman et al. 2011; Nagy and Aubert 2012). VAChT overexpression is therefore maintained at least up to 6 months in B6eGFPChAT mice without affecting ChAT and CHT expression. "
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    ABSTRACT: Cholinergic innervation is extensive throughout the central and peripheral nervous systems. Among its many roles, the neurotransmitter acetylcholine (ACh) contributes to the regulation of motor function, locomotion, and exploration. Cholinergic deficits and replacement strategies have been investigated in neurodegenerative disorders, particularly in cases of Alzheimer's disease (AD). Focus has been on blocking acetylcholinesterase (AChE) and enhancing ACh synthesis to improve cholinergic neurotransmission. As a first step in evaluating the physiological effects of enhanced cholinergic function through the upregulation of the vesicular acetylcholine transporter (VAChT), we used the hypercholinergic B6eGFPChAT congenic mouse model that has been shown to contain multiple VAChT gene copies. Analysis of biochemical and behavioral paradigms suggest that modest increases in VAChT expression can have a significant effect on spontaneous locomotion, reaction to novel stimuli, and the adaptation to novel environments. These observations support the potential of VAChT as a therapeutic target to enhance cholinergic tone, thereby decreasing spontaneous hyperactivity and increasing exploration in novel environments.
    Brain and Behavior 07/2013; 3(4):367-83. DOI:10.1002/brb3.139 · 2.24 Impact Factor
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