Vesicular Glutamate Transport Promotes Dopamine Storage and Glutamate Corelease In Vivo

Departments of Physiology and Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
Neuron (Impact Factor: 15.05). 03/2010; 65(5):643-56. DOI: 10.1016/j.neuron.2010.02.012
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Dopamine neurons in the ventral tegmental area (VTA) play an important role in the motivational systems underlying drug addiction, and recent work has suggested that they also release the excitatory neurotransmitter glutamate. To assess a physiological role for glutamate corelease, we disrupted the expression of vesicular glutamate transporter 2 selectively in dopamine neurons. The conditional knockout abolishes glutamate release from midbrain dopamine neurons in culture and severely reduces their excitatory synaptic output in mesoaccumbens slices. Baseline motor behavior is not affected, but stimulation of locomotor activity by cocaine is impaired, apparently through a selective reduction of dopamine stores in the projection of VTA neurons to ventral striatum. Glutamate co-entry promotes monoamine storage by increasing the pH gradient that drives vesicular monoamine transport. Remarkably, low concentrations of glutamate acidify synaptic vesicles more slowly but to a greater extent than equimolar Cl(-), indicating a distinct, presynaptic mechanism to regulate quantal size.

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    • " responses in CINs that were blocked by AMPA and NMDA receptor antagonists ( Chuhma et al . , 2014 ) . One explanation for the persistence of burst - pauses following direct activation of dopamine terminals in the presence of dopamine antagonism is the co - release of glutamate . However , this mechanism is prominent only in the ventral striatum ( Hnasko et al . , 2010 ; Stuber et al . , 2010 ) ; phasic optogenetic stimulation of dopaminergic terminals in the dorsal striatum accordingly did not evoke an initial burst response before the CIN firing pause ( Chuhma et al . , 2014 ) . Thus , the mechanisms underlying phasic burst firing of CINs in the dorsal striatum remain to be elucidated . CINs receive"
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    ABSTRACT: Pauses in the tonic firing of striatal cholinergic interneurons (CINs) emerge during reward-related learning in response to conditioning of a neutral cue. We have previously reported that augmenting the postsynaptic response to cortical afferents in CINs is coupled to the emergence of a cell-intrinsic afterhyperpolarization (AHP) underlying pauses in tonic activity. Here we investigated in a bihemispheric rat-brain slice preparation the mechanisms of synaptic plasticity of excitatory afferents to CINs and the association with changes in the AHP. We found that high frequency stimulation (HFS) of commissural corticostriatal afferents from the contralateral hemisphere induced a robust long-term depression (LTD) of postsynaptic potentials (PSP) in CINs. Depression of the PSP of smaller magnitude and duration was observed in response to HFS of the ipsilateral white matter or cerebral cortex. In Mg2+-free solution HFS induced NMDA receptor-dependent potentiation of the PSP, evident in both the maximal slope and amplitude of the PSP. The increase in maximal slope corroborates previous findings, and was blocked by antagonism of either D1-like dopamine receptors with SCH23390 or D2-like dopamine receptors with sulpiride during HFS in Mg2+-free solution. Potentiation of the slower PSP amplitude component was due to augmentation of the NMDA receptor-mediated potential as this was completely reversed on subsequent application of the NMDA receptor antagonist AP5. HFS similarly potentiated NMDA receptor currents isolated by blockade of AMPA/kainate receptors with CNQX. The plasticity-induced increase in the slow PSP component was directly associated with an increase in the subsequent AHP. Thus plasticity of cortical afferent synapses is ideally suited to influence the cue-induced firing dynamics of CINs, particularly through potentiation of NMDA receptor-mediated synaptic transmission.
    Frontiers in Cellular Neuroscience 04/2015; 9. DOI:10.3389/fncel.2015.00116 · 4.29 Impact Factor
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    • "Excitatory glutamatergic activity in the striatum originates mainly from frontal cortex, midline and intralaminar thalamus, basal amygdala, and hippocampus (reviewed in Sesack and Grace, 2010; Stuber et al., 2012). Additionally, DA terminals release glutamate (Sulzer et al., 1998; Joyce and Rayport, 2000; Sulzer and Rayport, 2000; Chuhma et al., 2004; Dal Bo et al., 2004; Chuhma et al., 2009; Hnasko et al., 2010), and this has recently been demonstrated by way of selective optogenetic stimulation of DA terminals (Stuber et al., 2010). However, this last report demonstrates that such possibility exists only in DA terminals that reach the NAc, not the dorsal striatum. "
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    ABSTRACT: The mesolimbic and nigrostriatal dopamine (DA) systems play a key role in the physiology of reward seeking, motivation and motor control. Importantly, they are also involved in the pathophysiology of Parkinson's and Huntington's disease, schizophrenia and addiction. Control of DA release in the striatum is tightly linked to firing of DA neurons in the ventral tegmental area (VTA) and the substantia nigra (SN). However, local influences in the striatum affect release by exerting their action directly on axon terminals. For example, endogenous glutamatergic and cholinergic activity is sufficient to trigger striatal DA release independently of cell body firing. Recent developments involving genetic manipulation, pharmacological selectivity or selective stimulation have allowed for better characterization of these phenomena. Such termino-terminal forms of control of DA release transform considerably our understanding of the mesolimbic and nigrostriatal systems, and have strong implications as potential mechanisms to modify impaired control of DA release in the diseased brain. Here, we review these and related mechanisms and their implications in the physiology of ascending DA systems.
    Frontiers in Behavioral Neuroscience 05/2014; 8:188. DOI:10.3389/fnbeh.2014.00188 · 3.27 Impact Factor
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    • "In our extended analysis of VGLUT2 at a midgestational embryonic stage (E12), we now show that this protein is found throughout the brain already at this early developmental stage, putatively supporting a broader role in establishment of the nervous system than previously recognized, but which could gain from further exploration. For gene targeting of Vglut2 expression within DA neurons specifically , DAT-Cre transgenic mice, of which there exists a couple of variants, have been used by breeding to floxed Vglut2 f/f mice, of which there also exist a few variants (Birgner et al. 2010; Fortin et al. 2012; Hnasko et al. 2010). Data have generally been interpreted based on the assumption that DAT-Cre will be active in all DA neurons and similar assumptions are common in neighbouring research fields where DAT-Cre mice are used to target other gene expression in DA neurons [e.g. the selective targeting of components of the glutamatergic machinery; reviewed in Rodriguez Parkitna and Engblom (2012)]. "
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    ABSTRACT: Three populations of neurons expressing the vesicular glutamate transporter 2 (Vglut2) were recently described in the A10 area of the mouse midbrain, of which two populations were shown to express the gene encoding, the rate-limiting enzyme for catecholamine synthesis, tyrosine hydroxylase (TH).One of these populations ("TH-Vglut2 Class1") also expressed the dopamine transporter (DAT) gene while one did not ("TH-Vglut2 Class2"), and the remaining population did not express TH at all ("Vglut2-only"). TH is known to be expressed by a promoter which shows two phases of activation, a transient one early during embryonal development, and a later one which gives rise to stable endogenous expression of the TH gene. The transient phase is, however, not specific to catecholaminergic neurons, a feature taken to advantage here as it enabled Vglut2 gene targeting within all three A10 populations expressing this gene, thus creating a new conditional knockout. These knockout mice showed impairment in spatial memory function. Electrophysiological analyses revealed a profound alteration of oscillatory activity in the CA3 region of the hippocampus. In addition to identifying a novel role for Vglut2 in hippocampus function, this study points to the need for improved genetic tools for targeting of the diversity of subpopulations of the A10 area.
    Brain Structure and Function 05/2014; 220(4). DOI:10.1007/s00429-014-0778-9 · 5.62 Impact Factor
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