Axonal Segregation and Role of the Vesicular Glutamate Transporter VGLUT3 in Serotonin Neurons

Voisin, Aurore; Mnie-Filali, Ouissame; Giguère, Nicolas; Fortin, Guillaume; Vigneault, Érika; Mestikawy, Salah El; Descarries, Laurent; Trudeau, Louis-Éric

doi:10.3389/fnana.2016.00039

Cited by 23 publications

(29 citation statements)

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“…5c). This reduction is well in line with the previously described loss of vesicular synergy in VGLUT3-KO mice (Amilhon et al 2010;Voisin et al 2016).…”

Section: Deletion Of Vglut3 In 5-ht Neurons Does Not Affect Amphetamisupporting

confidence: 92%

VGLUT3 gates psychomotor effects induced by amphetamine

Mansouri-Guilani

Bernard

Vigneault

et al. 2019

Journal of Neurochemistry

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Several subtypes of modulatory neurons co‐express vesicular glutamate transporters (VGLUTs) in addition to their cognate vesicular transporters. These neurons are believed to establish new forms of neuronal communication. The atypical VGLUT3 is of particular interest since in the striatum this subtype is found in tonically active cholinergic interneurons (TANs) and in a subset of 5‐HT fibers. The striatum plays a major role in psychomotor effects induced by amphetamine. Whether and how VGLUT3‐operated glutamate/ACh or glutamate/5HT co‐transmissions modulates psychostimulants‐induced maladaptive behaviors is still unknown. Here, we investigate the involvement of VGLUT3 and glutamate co‐transmission in amphetamine‐induced psychomotor effects and stereotypies. Taking advantage of constitutive and cell‐type specific VGLUT3‐deficient mouse lines, we tackled the hypothesis that VGLUT3 could gate psychomotor effects (locomotor activity and stereotypies) induced by acute or chronic administration of amphetamine. Interestingly, VGLUT3‐null mice demonstrated blunted amphetamine‐induced stereotypies as well as reduced striatal ∆FosB expression. VGLUT3‐positive varicosities within the striatum arise in part from 5HT neurons. We tested the involvement of VGLUT3 deletion in serotoninergic neurons in amphetamine‐induced stereotypies. Mice lacking VGLUT3 specifically in 5HT fibers showed no alteration to amphetamine sensitivity. In contrast, specific deletion of VGLUT3 in cholinergic neurons partially phenocopied the effects observed in the constitutive knock‐out mice. Our results show that constitutive deletion of VGLUT3 modulates acute and chronic locomotor effects induced by amphetamine. They point to the fact that the expression of VGLUT3 in multiple brain areas is pivotal in gating amphetamine‐induced psychomotor adaptations. Open Science Badges This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

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“…5c). This reduction is well in line with the previously described loss of vesicular synergy in VGLUT3-KO mice (Amilhon et al 2010;Voisin et al 2016).…”

Section: Deletion Of Vglut3 In 5-ht Neurons Does Not Affect Amphetamisupporting

confidence: 92%

VGLUT3 gates psychomotor effects induced by amphetamine

Mansouri-Guilani

Bernard

Vigneault

et al. 2019

Journal of Neurochemistry

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“…This heroin-induced activation may be achieved by disinhibiting serotonin neurons through reducing local GABAergic activity 43 , 44 . Given that some DRN serotonin neurons may corelease glutamate 8 , 45 , some heroin-associate behaviors might be mediated by serotonin and the potentially coreleased glutamate.…”

Section: Discussionmentioning

confidence: 99%

Response dynamics of midbrain dopamine neurons and serotonin neurons to heroin, nicotine, cocaine, and MDMA

Wei

Han²,

Weng

et al. 2018

Cell Discov

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Heroin, nicotine, cocaine, and MDMA are abused by billions of people. They are believed to target midbrain dopamine neurons and/or serotonin neurons, but their effects on the dynamic neuronal activity remain unclear in behaving states. By combining cell-type-specific fiber photometry of Ca2+ signals and intravenous drug infusion, here we show that these four drugs of abuse profoundly modulate the activity of mouse midbrain dopamine neurons and serotonin neurons with distinct potency and kinetics. Heroin strongly activates dopamine neurons, and only excites serotonin neurons at higher doses. Nicotine activates dopamine neurons in merely a few seconds, but produces minimal effects on serotonin neurons. Cocaine and MDMA cause long-lasting suppression of both dopamine neurons and serotonin neurons, although MDMA inhibits serotonin neurons more profoundly. Moreover, these inhibitory effects are mediated through the activity of dopamine and serotonin autoreceptors. These results suggest that the activity of dopamine neurons and that of serotonin neurons are more closely associated with the drug's reinforcing property and the drug's euphorigenic property, respectively. This study also shows that our methodology may facilitate further in-vivo interrogation of neural dynamics using animal models of drug addiction.

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“…The functional implications of VGLUT3 in serotonergic neurons are unclear, although several possibilities have been suggested: 1) glutamate is used as a transmitter in 5-HT neurons—either via co-release with 5-HT at the same terminals (Gagnon and Parent, 2014) or via segregated release from different terminals (Amilhon et al, 2010), 2) VGLUT3 enhances the efficiency of serotonin signaling by facilitating vesicular packaging of 5-HT (Amilhon et al, 2010), and 3) VGLUT3 may adjust the ratio of synaptic transmission to volume transmission along serotonergic axons by promoting the formation of synaptic specializations (Gagnon and Parent, 2014; Voisin et al, 2016). A study using cultured mesopontine 5-HT neurons found that those from a VGLUT3 knockout mouse had a significantly lower basal survival rate compared to serotonergic cells from wild-type littermates (Voisin et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…A study using cultured mesopontine 5-HT neurons found that those from a VGLUT3 knockout mouse had a significantly lower basal survival rate compared to serotonergic cells from wild-type littermates (Voisin et al, 2016). The authors of that study suggest that VGLUT3 may regulate serotonergic neuronal development or confer general fitness to 5-HT neurons; such functions could explain the presence of VGLUT3 in nearly all DR 5-HT cell bodies that we observed (Voisin et al, 2016). …”

Section: Discussionmentioning

confidence: 99%

“…The unique localization of the VGLUT3 isoform within cell bodies makes it an ideal neurochemical marker for co-localization studies to identify serotonergic projection neurons that may be capable of releasing glutamate. The co-release of 5-HT and glutamate would have major implications for activity-dependent plasticity in target circuits and recent evidence suggests that VGLUT3 itself may influence 5-HT transmission by enhancing vesicular packing of 5-HT (Amilhon et al, 2010) or regulating the number of synaptic specializations formed by serotonergic axons (Gagnon and Parent, 2014; Voisin et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

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Neurochemical differences between target-specific populations of rat dorsal raphe projection neurons

2017

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Serotonin (5-HT)-containing neurons in the dorsal raphe (DR) nucleus project throughout the forebrain and are implicated in many physiological processes and neuropsychiatric disorders. Diversity among these neurons has been characterized in terms of their neurochemistry and anatomical organization, but a clear sense of whether these attributes align with specific brain functions or terminal fields is lacking. DR 5-HT neurons can co-express additional neuroactive substances, increasing the potential for individualized regulation of target circuits. The goal of this study was to link DR neurons to a specific functional role by characterizing cells according to both their neurotransmitter expression and efferent connectivity; specifically, cells projecting to the medial prefrontal cortex (mPFC), a region implicated in cognition, emotion, and responses to stress. Following retrograde tracer injection, brainstem sections from Sprague-Dawley rats were immunohistochemically stained for markers of serotonin, glutamate, GABA, and nitric oxide (NO). 98% of the mPFC-projecting serotonergic neurons co-expressed the marker for glutamate, while the markers for NO and GABA were observed in 60% and less than 1% of those neurons, respectively. To identify potential target-specific differences in co-transmitter expression, we also characterized DR neurons projecting to a visual sensory structure, the lateral geniculate nucleus (LGN). The proportion of serotonergic neurons co-expressing NO was greater amongst cells targeting the mPFC vs LGN (60% vs 22%). The established role of 5-HT in affective disorders and the emerging role of NO in stress signaling suggest that the impact of 5-HT/NO co-localization in DR neurons that regulate mPFC circuit function may be clinically relevant.

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Axonal Segregation and Role of the Vesicular Glutamate Transporter VGLUT3 in Serotonin Neurons

Cited by 23 publications

References 50 publications

VGLUT3 gates psychomotor effects induced by amphetamine

VGLUT3 gates psychomotor effects induced by amphetamine

Response dynamics of midbrain dopamine neurons and serotonin neurons to heroin, nicotine, cocaine, and MDMA

Neurochemical differences between target-specific populations of rat dorsal raphe projection neurons

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