Article

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

ABSTRACT

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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    • "Thus, providing that cortical cholinergic projections are intact, hippocampal cholinergic activity is not absolutely required for this behavioral task. It remains to be established whether GABA or glutamate, which could potentially be co-released with ACh (Guzman et al. 2011;Saunders et al. 2015) in both the hippocampus and cortex, may contribute to regulation of spatial memory by cholinergic neurons. In contrast to the reference memory test, both VAChT Nkx2.1-Cre-flox/ flox and AAV8-GFP-Cre-GFP-injected mice when tested in the MWM reversal learning task presented extensive deficits, suggesting a prominent role for hippocampal cholinergic signaling in reversal learning. "
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    ABSTRACT: Cholinergic dysfunction has been associated with cognitive abnormalities in a variety of neurodegenerative and neuropsychiatric diseases. Here we tested how information processing is regulated by cholinergic tone in genetically modified mice targeting the vesicular acetylcholine transporter (VAChT), a protein required for acetylcholine release. We measured long-term potentiation of Schaffer collateral-CA1 synapses in vivo and assessed information processing by using a mouse touchscreen version of paired associates learning task (PAL). Acquisition of information in the mouse PAL task correlated to levels of hippocampal VAChT, suggesting a critical role for cholinergic tone. Accordingly, synaptic plasticity in the hippocampus in vivo was disturbed, but not completely abolished, by decreased hippocampal cholinergic signaling. Disrupted forebrain cholinergic signaling also affected working memory, a result reproduced by selectively decreasing VAChT in the hippocampus. In contrast, spatial memory was relatively preserved, whereas reversal spatial memory was sensitive to decreased hippocampal cholinergic signaling. This work provides a refined roadmap of how synaptically secreted acetylcholine influences distinct behaviors and suggests that distinct forms of cognitive processing may be regulated in different ways by cholinergic activity.
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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.
    Full-text · Article · Nov 2013 · PLoS ONE
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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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