@article{pmid42504398,

title = {Phenotypic Behavioural Effects of Genetic Deletion of the Vesicular Glutamate Transporter 3 in 5-Hydroxytryptamine Neurons},

author = {L Sophie Gullino and Nida Chabbah and Spatika Jayaram and Raquel Pinacho and Salah El Mestikawy and Stéphanie Daumas and David M Bannerman and Trevor Sharp},

doi = {10.1111/gbb.70063},

issn = {1601-183X},

year  = {2026},

date = {2026-08-01},

journal = {Genes Brain Behav},

volume = {25},

number = {4},

pages = {e70063},

abstract = {A major subpopulation of 5-hydroxytryptamine (5-HT) neurons expresses the vesicular glutamate transporter 3 (VGLUT3) allowing the co-release of glutamate. Previous evidence has implicated VGLUT3 in 5-HT neurons in mechanisms of anxiety and reward. Here we examined mice with a genetic loss of VGLUT3 targeted to 5-HT neurons (VGLUT3 cKO) and littermate controls in a battery of behavioural tests, including paradigms assessing levels of anxiety and learning with appetitive rewards. Compared to littermate controls, VGLUT3 cKO mice displayed no evidence of altered anxiety-like behaviour in the elevated plus maze, light/dark box, marble burying and social interaction tests. However, VGLUT3 cKO mice showed reduced preference for low (but not high) sucrose-containing solution and reduced correct responses in an appetitively motivated spatial reference memory task. Similarly, in an appetitively motivated operant task, VGLUT3 cKO mice displayed evidence of reduced responding to cues associated with reward. These effects appeared specific in that VGLUT3 cKO mice did not differ from controls in terms of home cage food consumption, performance in a spatial novelty preference test, as well as contextual and cued fear memory tests. These findings support a role for VGLUT3 in 5-HT neurons in some aspects of learning, here in association with learning for reward, although not anxiety-like behaviour.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39810425,

title = {Synaptic Targets and Cellular Sources of CB1 Cannabinoid Receptor and Vesicular Glutamate Transporter-3 Expressing Nerve Terminals in Relation to GABAergic Neurons in the Human Cerebral Cortex},

author = {Peter Somogyi and Sawa Horie and Istvan Lukacs and Emily Hunter and Barbara Sarkany and Tim James Viney and James Livermore and Puneet Plaha and Richard Stacey and Olaf Ansorge and Salah El Mestikawy and Qianru Zhao},

doi = {10.1111/ejn.16652},

issn = {1460-9568},

year  = {2025},

date = {2025-01-01},

journal = {Eur J Neurosci},

volume = {61},

number = {1},

pages = {e16652},

abstract = {Cannabinoid receptor 1 (CB1) regulates synaptic transmission through presynaptic receptors in nerve terminals, and its physiological roles are of clinical relevance. The cellular sources and synaptic targets of CB1-expressing terminals in the human cerebral cortex are undefined. We demonstrate a variable laminar pattern of CB1-immunoreactive axons and electron microscopically show that CB1-positive GABAergic terminals make type-2 synapses innervating dendritic shafts (69%), dendritic spines (20%) and somata (11%) in neocortical layers 2-3. Of the CB1-immunopositive GABAergic terminals, 25% were vesicular-glutamate-transporter-3 (VGLUT3)-immunoreactive, suggesting GABAergic/glutamatergic co-transmission on dendritic shafts. In vitro recorded and labelled VGLUT3 or CB1-positive GABAergic interneurons expressed cholecystokinin, vasoactive-intestinal-polypeptide and calretinin, had diverse firing, axons and dendrites, and included rosehip, neurogliaform and basket cells, but not double bouquet or axo-axonic cells. CB1-positive interneurons innervated pyramidal cells and GABAergic interneurons. Glutamatergic synaptic terminals formed type-1 synapses and some were positive for CB1 receptor with a distribution that appeared different from that in GABAergic terminals. From the sampled VGLUT3-positive terminals, 60% formed type-1 synapses with dendritic spines (80%) or shafts (20%) and 52% were also positive for VGLUT1, suggesting intracortical origin. Some VGLUT3-positive terminals were immunopositive for vesicular-monoamine-transporter-2, suggesting 5-HT/glutamate co-transmission. Overall, the results show that CB1 regulates GABA release mainly to dendritic shafts of both pyramidal cells and interneurons and predict CB1-regulated co-release of GABA and glutamate from single cortical interneurons. We also demonstrate the co-existence of multiple vesicular glutamate transporters in a select population of terminals probably originating from cortical neurons and innervating dendritic spines in the human cerebral cortex.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39432105,

title = {Exploring the efficacy of cholinergic agents for the treatment of psychostimulant use disorder: a systematic review},

author = {Nicolas Salloum and Margot Chouchana and Romain Icick and Vanessa Bloch and Stéphanie Daumas and Salah El Mestikawy and Florence Vorspan and Virgile Clergue-Duval},

doi = {10.1007/s00213-024-06696-5},

issn = {1432-2072},

year  = {2024},

date = {2024-11-01},

journal = {Psychopharmacology (Berl)},

volume = {241},

number = {11},

pages = {2205--2222},

abstract = {RATIONALE: No drugs are currently validated to treat psychostimulant use disorder (PUD). Pathophysiological studies consistently highlight the contribution of cholinergic mechanisms in psychostimulant use, including the vulnerability to PUD, paving the way for potential therapeutic strategies.nnOBJECTIVES: The aim of this systematic review is to describe and discuss the efficacy of cholinergic agents in drug trials for patients with PUD.nnMETHODS: A systematic review was conducted on April 4, 2024 in MedLine, Embase and Cochrane Library databases on controlled clinical drug trial of cholinergic agents in humans with PUD, psychostimulant abuse or dependence and psychostimulant use in recent year.nnRESULTS: Twenty-eight articles were included, twenty-one on cocaine and seven on amphetamines. Cholinergic agents used in these studies were biperiden (a muscarinic antagonist), mecamylamine (a nicotinic antagonist), nicotinic agonists, acetylcholinesterase inhibitors (AChEI), or citicoline. Two types of trials were identified. There were seventeen randomized controlled clinical trials evaluating cholinergic agents on psychostimulant use reduction in outpatients seeking treatment. Additionally, we retrieved eleven short-term «proof-of-concept» laboratory trials mainly with supervised psychostimulant administration and/or triggered craving challenges. Outpatient trials were heterogeneous and for most, inconclusive. Only two studies on galantamine (AChEI) and citicoline, reported a significant reduction of cocaine consumption. «Proof-of-concept» laboratory trials showed no evidence of efficacy on the selected outcomes, notably on craving.nnCONCLUSIONS: This review does not support the current prescription of cholinergic agents to treat PUD. Replication clinical trials notably on galantamine or other AChEI, and proof-of-concept trials on comedown symptoms will be necessary to identify a potential therapeutic indication for cholinergic agents in PUD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38944834,

title = {Regulation of stress-induced sleep perturbations by dorsal raphe VGLUT3 neurons in male mice},

author = {Fiona Henderson and Sylvie Dumas and Giuseppe Gangarossa and Véronique Bernard and Marine Pujol and Odile Poirel and Nicolas Pietrancosta and Salah El Mestikawy and Stéphanie Daumas and Véronique Fabre},

doi = {10.1016/j.celrep.2024.114411},

issn = {2211-1247},

year  = {2024},

date = {2024-07-01},

journal = {Cell Rep},

volume = {43},

number = {7},

pages = {114411},

abstract = {Exposure to stressors has profound effects on sleep that have been linked to serotonin (5-HT) neurons of the dorsal raphe nucleus (DR). However, the DR also comprises glutamatergic neurons expressing vesicular glutamate transporter type 3 (DR), leading us to examine their role. Cell-type-specific tracing revealed that DR neurons project to brain areas regulating arousal and stress. We found that chemogenetic activation of DR neurons mimics stress-induced sleep perturbations. Furthermore, deleting VGLUT3 in the DR attenuated stress-induced sleep perturbations, especially after social defeat stress. In the DR, VGLUT3 is found in subsets of 5-HT and non-5-HT neurons. We observed that both populations are activated by acute stress, including those projecting to the ventral tegmental area. However, deleting VGLUT3 in 5-HT neurons minimally affected sleep regulation. These findings suggest that VGLUT3 expression in the DR drives stress-induced sleep perturbations, possibly involving non-5-HT DR neurons.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38971801,

title = {The human VGLUT3-pT8I mutation elicits uneven striatal DA signaling, food or drug maladaptive consumption in male mice},

author = {Mathieu Favier and Elena Martin Garcia and Romain Icick and Camille de Almeida and Joachim Jehl and Mazarine Desplanque and Johannes Zimmermann and Annabelle Henrion and Nina Mansouri-Guilani and Coline Mounier and Svethna Ribeiro and Fiona Henderson and Andrea Geoffroy and Sebastien Mella and Odile Poirel and Véronique Bernard and Véronique Fabre and Yulong Li and Christian Rosenmund and Stéphane Jamain and Florence Vorspan and Alexandre Mourot and Philibert Duriez and Leora Pinhas and Rafael Maldonado and Nicolas Pietrancosta and Stéphanie Daumas and Salah El Mestikawy},

doi = {10.1038/s41467-024-49371-1},

issn = {2041-1723},

year  = {2024},

date = {2024-07-01},

journal = {Nat Commun},

volume = {15},

number = {1},

pages = {5691},

abstract = {Cholinergic striatal interneurons (ChIs) express the vesicular glutamate transporter 3 (VGLUT3) which allows them to regulate the striatal network with glutamate and acetylcholine (ACh). In addition, VGLUT3-dependent glutamate increases ACh vesicular stores through vesicular synergy. A missense polymorphism, VGLUT3-p.T8I, was identified in patients with substance use disorders (SUDs) and eating disorders (EDs). A mouse line was generated to understand the neurochemical and behavioral impact of the p.T8I variant. In VGLUT3 male mice, glutamate signaling was unchanged but vesicular synergy and ACh release were blunted. Mutant male mice exhibited a reduced DA release in the dorsomedial striatum but not in the dorsolateral striatum, facilitating habit formation and exacerbating maladaptive use of drug or food. Increasing ACh tone with donepezil reversed the self-starvation phenotype observed in VGLUT3 male mice. Our study suggests that unbalanced dopaminergic transmission in the dorsal striatum could be a common mechanism between SUDs and EDs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38377469,

title = {Evidence for a Role of 5-HT-glutamate Co-releasing Neurons in Acute Stress Mechanisms},

author = {L Sophie Gullino and Cara Fuller and Poppy Dunn and Helen M Collins and Salah El Mestikawy and Trevor Sharp},

doi = {10.1021/acschemneuro.3c00758},

issn = {1948-7193},

year  = {2024},

date = {2024-03-01},

journal = {ACS Chem Neurosci},

volume = {15},

number = {6},

pages = {1185--1196},

abstract = {A major subpopulation of midbrain 5-hydroxytryptamine (5-HT) neurons expresses the vesicular glutamate transporter 3 (VGLUT3) and co-releases 5-HT and glutamate, but the function of this co-release is unclear. Given the strong links between 5-HT and uncontrollable stress, we used a combination of c-Fos immunohistochemistry and conditional gene knockout mice to test the hypothesis that glutamate co-releasing 5-HT neurons are activated by stress and involved in stress coping. Acute, uncontrollable swim stress increased c-Fos immunoreactivity in neurons co-expressing VGLUT3 and the 5-HT marker tryptophan hydroxylase 2 (TPH2) in the dorsal raphe nucleus (DRN). This effect was localized in the ventral DRN subregion and prevented by the antidepressant fluoxetine. In contrast, a more controllable stressor, acute social defeat, had no effect on c-Fos immunoreactivity in VGLUT3-TPH2 co-expressing neurons in the DRN. To test whether activation of glutamate co-releasing 5-HT neurons was causally linked to stress coping, mice with a specific deletion of VGLUT3 in 5-HT neurons were exposed to acute swim stress. Compared to wildtype controls, the mutant mice showed increased climbing behavior, a measure of active coping. Wildtype mice also showed increased climbing when administered fluoxetine, revealing an interesting parallel between the behavioral effects of genetic loss of VGLUT3 in 5-HT neurons and 5-HT reuptake inhibition. We conclude that 5-HT-glutamate co-releasing neurons are recruited by exposure to uncontrollable stress. Furthermore, natural variation in the balance of 5-HT and glutamate co-released at the 5-HT synapse may impact stress susceptibility.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37055181,

title = {VGLUT3 Deletion Rescues Motor Deficits and Neuronal Loss in the zQ175 Mouse Model of Huntington's Disease},

author = {Karim S Ibrahim and Salah El Mestikawy and Khaled S Abd-Elrahman and Stephen S G Ferguson},

doi = {10.1523/JNEUROSCI.0014-23.2023},

issn = {1529-2401},

year  = {2023},

date = {2023-06-01},

journal = {J Neurosci},

volume = {43},

number = {23},

pages = {4365--4377},

abstract = {Huntington's disease (HD) is an autosomal-dominant neurodegenerative disease characterized by progressive motor and cognitive impairments, with no disease-modifying therapies yet available. HD pathophysiology involves evident impairment in glutamatergic neurotransmission leading to severe striatal neurodegeneration. The vesicular glutamate transporter-3 (VGLUT3) regulates the striatal network that is centrally affected by HD. Nevertheless, current evidence on the role of VGLUT3 in HD pathophysiology is lacking. Here, we crossed mice lacking  gene ( ) with heterozygous  knock-in mouse model of HD ( ). Longitudinal assessment of motor and cognitive functions from 6 to 15 months of age reveals that VGLUT3 deletion rescues motor coordination and short-term memory deficits in both male and female  mice. VGLUT3 deletion also rescues neuronal loss likely via the activation of Akt and ERK1/2 in the striatum of  mice of both sexes. Interestingly, the rescue in neuronal survival in   mice is accompanied by a reduction in the number of nuclear mutant huntingtin (mHTT) aggregates with no change in the total aggregate levels or microgliosis. Collectively, these findings provide novel evidence that VGLUT3, despite its limited expression, can be a vital contributor to HD pathophysiology and a viable target for HD therapeutics. Dysregulation of the striatal network centrally contributes to the pathophysiology of Huntington's disease (HD). The atypical vesicular glutamate transporter-3 (VGLUT3) has been shown to regulate several major striatal pathologies, such as addiction, eating disorders, or L-DOPA-induced dyskinesia. Yet, our understanding of VGLUT3's role in HD remains unclear. We report here that deletion of the  () gene rescues the deficits in both motor and cognitive functions in HD mice of both sexes. We also find that VGLUT3 deletion activates neuronal survival signaling and reduces nuclear aggregation of abnormal huntingtin proteins and striatal neuron loss in HD mice. Our novel findings highlight the vital contribution of VGLUT3 in HD pathophysiology that can be exploited for HD therapeutic management.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36720646,

title = {Absence of VGLUT3 Expression Leads to Impaired Fear Memory in Mice},

author = {Camille de Almeida and Nida Chabbah and Camille Eyraud and Caroline Fasano and Véronique Bernard and Nicolas Pietrancosta and Véronique Fabre and Salah El Mestikawy and Stephanie Daumas},

doi = {10.1523/ENEURO.0304-22.2023},

issn = {2373-2822},

year  = {2023},

date = {2023-02-01},

journal = {eNeuro},

volume = {10},

number = {2},

abstract = {Fear is an emotional mechanism that helps to cope with potential hazards. However, when fear is generalized, it becomes maladaptive and represents a core symptom of posttraumatic stress disorder (PTSD). Converging lines of research show that dysfunction of glutamatergic neurotransmission is a cardinal feature of trauma and stress related disorders such as PTSD. However, the involvement of glutamatergic co-transmission in fear is less well understood. Glutamate is accumulated into synaptic vesicles by vesicular glutamate transporters (VGLUTs). The atypical subtype, VGLUT3, is responsible for the co-transmission of glutamate with acetylcholine, serotonin, or GABA. To understand the involvement of VGLUT3-dependent co-transmission in aversive memories, we used a Pavlovian fear conditioning paradigm in VGLUT3 mice. Our results revealed a higher contextual fear memory in these mice, despite a facilitation of extinction. In addition, the absence of VGLUT3 leads to fear generalization, probably because of a pattern separation deficit. Our study suggests that the VGLUT3 network plays a crucial role in regulating emotional memories. Hence, VGLUT3 is a key player in the processing of aversive memories and therefore a potential therapeutic target in stress-related disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37624765,

title = {Persistent extrasynaptic hyperdopaminergia in the mouse hippocampus induces plasticity and recognition memory deficits reversed by the atypical antipsychotic sulpiride},

author = {Jill Rocchetti and Caroline Fasano and Gregory Dal-Bo and Elisa Guma and Salah El Mestikawy and Tak-Pan Wong and Gohar Fakhfouri and Bruno Giros},

doi = {10.1371/journal.pone.0289770},

issn = {1932-6203},

year  = {2023},

date = {2023-01-01},

journal = {PLoS One},

volume = {18},

number = {8},

pages = {e0289770},

abstract = {Evidence suggests that subcortical hyperdopaminergia alters cognitive function in schizophrenia and antipsychotic drugs (APD) fail at rescuing cognitive deficits in patients. In a previous study, we showed that blocking D2 dopamine receptors (D2R), a core action of APD, led to profound reshaping of mesohippocampal fibers, deficits in synaptic transmission and impairments in learning and memory in the mouse hippocampus (HP). However, it is currently unknown how excessive dopamine affects HP-related cognitive functions, and how APD would impact HP functions in such a state. After verifying the presence of DAT-positive neuronal projections in the ventral (temporal), but not in the dorsal (septal), part of the HP, GBR12935, a blocker of dopamine transporter (DAT), was infused in the CA1 of adult C57Bl/6 mice to produce local hyperdopaminergia. Chronic GBR12935 infusion in temporal CA1 induced a mild learning impairment in the Morris Water Maze and abolished long-term recognition memory in novel-object (NORT) and object-place recognition tasks (OPRT). Deficits were accompanied by a significant decrease in DAT+ mesohippocampal fibers. Intrahippocampal or systemic treatment with sulpiride during GBR infusions improved the NORT deficit but not that of OPRT. In vitro application of GBR on hippocampal slices abolished long-term depression (LTD) of fEPSP in temporal CA1. LTD was rescued by co-application with sulpiride. In conclusion, chronic DAT blockade in temporal CA1 profoundly altered mesohippocampal modulation of hippocampal functions. Contrary to previous observations in normodopaminergic mice, antagonising D2Rs was beneficial for cognitive functions in the context of hippocampal hyperdopaminergia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35173173,

title = {Disruption of the grid cell network in a mouse model of early Alzheimer's disease},

author = {Johnson Ying and Alexandra T Keinath and Raphael Lavoie and Erika Vigneault and Salah El Mestikawy and Mark P Brandon},

doi = {10.1038/s41467-022-28551-x},

issn = {2041-1723},

year  = {2022},

date = {2022-02-01},

journal = {Nat Commun},

volume = {13},

number = {1},

pages = {886},

abstract = {Early-onset familial Alzheimer's disease (AD) is marked by an aggressive buildup of amyloid beta (Aβ) proteins, yet the neural circuit operations impacted during the initial stages of Aβ pathogenesis remain elusive. Here, we report a coding impairment of the medial entorhinal cortex (MEC) grid cell network in the J20 transgenic mouse model of familial AD that over-expresses Aβ throughout the hippocampus and entorhinal cortex. Grid cells showed reduced spatial periodicity, spatial stability, and synchrony with interneurons and head-direction cells. In contrast, the spatial coding of non-grid cells within the MEC, and place cells within the hippocampus, remained intact. Grid cell deficits emerged at the earliest incidence of Aβ fibril deposition and coincided with impaired spatial memory performance in a path integration task. These results demonstrate that widespread Aβ-mediated damage to the entorhinal-hippocampal circuit results in an early impairment of the entorhinal grid cell network.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35032355,

title = {Functional dissociation of behavioral effects from acetylcholine and glutamate released from cholinergic striatal interneurons},

author = {Ornela Kljakic and Helena Janíčková and Miguel Skirzewski and Amy Reichelt and Sara Memar and Salah El Mestikawy and Yulong Li and Lisa M Saksida and Timothy J Bussey and Vania F Prado and Marco A M Prado},

doi = {10.1096/fj.202101425R},

issn = {1530-6860},

year  = {2022},

date = {2022-02-01},

journal = {FASEB J},

volume = {36},

number = {2},

pages = {e22135},

abstract = {In the striatum, cholinergic interneurons (CINs) have the ability to release both acetylcholine and glutamate, due to the expression of the vesicular acetylcholine transporter (VAChT) and the vesicular glutamate transporter 3 (VGLUT3). However, the relationship these neurotransmitters have in the regulation of behavior is not fully understood. Here we used reward-based touchscreen tests in mice to assess the individual and combined contributions of acetylcholine/glutamate co-transmission in behavior. We found that reduced levels of the VAChT from CINs negatively impacted dopamine signalling in response to reward, and disrupted complex responses in a sequential chain of events. In contrast, diminished VGLUT3 levels had somewhat opposite effects. When mutant mice were treated with haloperidol in a cue-based task, the drug did not affect the performance of VAChT mutant mice, whereas VGLUT3 mutant mice were highly sensitive to haloperidol. In mice where both vesicular transporters were deleted from CINs, we observed altered reward-evoked dopaminergic signalling and behavioral deficits that resemble, but were worse, than those in mice with specific loss of VAChT alone. These results demonstrate that the ability to secrete two different neurotransmitters allows CINs to exert complex modulation of a wide range of behaviors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36176961,

title = {Nanoscopic distribution of VAChT and VGLUT3 in striatal cholinergic varicosities suggests colocalization and segregation of the two transporters in synaptic vesicles},

author = {Paola Cristofari and Mazarine Desplanque and Odile Poirel and Alison Hébert and Sylvie Dumas and Etienne Herzog and Lydia Danglot and David Geny and Jean-François Gilles and Audrey Geeverding and Susanne Bolte and Alexis Canette and Michaël Trichet and Véronique Fabre and Stéphanie Daumas and Nicolas Pietrancosta and Salah El Mestikawy and Véronique Bernard},

doi = {10.3389/fnmol.2022.991732},

issn = {1662-5099},

year  = {2022},

date = {2022-01-01},

journal = {Front Mol Neurosci},

volume = {15},

pages = {991732},

abstract = {Striatal cholinergic interneurons (CINs) use acetylcholine (ACh) and glutamate (Glut) to regulate the striatal network since they express vesicular transporters for ACh (VAChT) and Glut (VGLUT3). However, whether ACh and Glut are released simultaneously and/or independently from cholinergic varicosities is an open question. The answer to that question requires the multichannel detection of vesicular transporters at the level of single synaptic vesicle (SV). Here, we used super-resolution STimulated Emission Depletion microscopy (STED) to characterize and quantify the distribution of VAChT and VGLUT3 in CINs SVs. Nearest-neighbor distances analysis between VAChT and VGLUT3-immunofluorescent spots revealed that 34% of CINs SVs contain both VAChT and VGLUT3. In addition, 40% of SVs expressed only VAChT while 26% of SVs contain only VGLUT3. These results suggest that SVs from CINs have the potential to store simultaneously or independently ACh and/or Glut. Overall, these morphological findings support the notion that CINs varicosities can signal with either ACh or Glut or both with an unexpected level of complexity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35937057,

title = {Reduced Metabotropic Glutamate Receptor Type 5 Availability in the Epileptogenic Hippocampus: An  Study},

author = {Maria Zimmermann and Luciano Minuzzi and Arturo Aliaga Aliaga and Marie-Christine Guiot and Jeffery A Hall and Jean-Paul Soucy and Gassan Massarweh and Salah El Mestikawy and Pedro Rosa-Neto and Eliane Kobayashi},

doi = {10.3389/fneur.2022.888479},

issn = {1664-2295},

year  = {2022},

date = {2022-01-01},

journal = {Front Neurol},

volume = {13},

pages = {888479},

abstract = {Abnormalities in the expression of metabotropic glutamate receptor type 5 (mGluR5) have been observed in the hippocampus of patients with drug-resistant mesial Temporal Lobe Epilepsy (mTLE).  studies in mTLE hippocampal surgical specimens have shown increased mGluR5 immunoreactivity, while  whole brain imaging using positron emission tomography (PET) demonstrated reduced hippocampal mGluR5 availability. To further understand mGluR5 abnormalities in mTLE, we performed a saturation autoradiography study with [H]ABP688 (a negative mGluR5 allosteric modulator). We aimed to evaluate receptor density (B) and dissociation constants (K) in hippocampal mTLE surgical specimens and in non-epilepsy hippocampi from necropsy controls. mTLE specimens showed a 43.4% reduction in receptor density compared to control hippocampi, which was independent of age, sex and K (multiple linear regression analysis). There was no significant difference in K between the groups, which suggests that the decreased mGluR5 availability found  with PET cannot be attributed to reduced affinity between ligand and binding site. The present study supports that changes within the epileptogenic tissue include mGluR5 internalization or conformational changes that reduce [H]ABP688 binding, as previously suggested in mTLE patients studied .},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35443989,

title = {VGLUT3 Ablation Differentially Modulates Glutamate Receptor Densities in Mouse Brain},

author = {Karim S Ibrahim and Salah El Mestikawy and Khaled S Abd-Elrahman and Stephen S G Ferguson},

doi = {10.1523/ENEURO.0041-22.2022},

issn = {2373-2822},

year  = {2022},

date = {2022-01-01},

journal = {eNeuro},

volume = {9},

number = {3},

abstract = {Type 3 vesicular glutamate transporter (VGLUT3) represents a unique modulator of glutamate release from both nonglutamatergic and glutamatergic varicosities within the brain. Despite its limited abundance, VGLUT3 is vital for the regulation of glutamate signaling and, therefore, modulates the activity of various brain microcircuits. However, little is known about how glutamate receptors are regulated by VGLUT3 across different brain regions. Here, we used VGLUT3 constitutive knock-out (VGLUT3) mice and explored how VGLUT3 deletion influences total and cell surface expression of different ionotropic and metabotropic glutamate receptors. VGLUT3 deletion upregulated the overall expression of metabotropic glutamate receptors mGluR5 and mGluR2/3 in the cerebral cortex. In contrast, no change in the total expression of ionotropic NMDAR glutamate receptors were observed in the cerebral cortex of VGLUT3 mice. We noted significant reduction in cell surface levels of mGluR5, NMDAR2A, NMDAR2B, as well as reductions in dopaminergic D receptors and muscarinic M1 acetylcholine receptors in the hippocampus of VGLUT3 mice. Furthermore, mGluR2/3 total expression and mGluR5 cell surface levels were elevated in the striatum of VGLUT3 mice. Last, AMPAR subunit GluA1 was significantly upregulated throughout cortical, hippocampal, and striatal brain regions of VGLUT3 mice. Together, these findings complement and further support the evidence that VGLUT3 dynamically regulates glutamate receptor densities in several brain regions. These results suggest that VGLUT3 may play an intricate role in shaping glutamatergic signaling and plasticity in several brain areas.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34783032,

title = {VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons},

author = {Yuvraj Joshi and Chloé P Petit and Stéphanie Miot and Marie Guillet and Gaston Sendin and Jérôme Bourien and Jing Wang and Rémy Pujol and Salah El Mestikawy and Jean-Luc Puel and Régis Nouvian},

doi = {10.1113/JP282181},

issn = {1469-7793},

year  = {2021},

date = {2021-12-01},

journal = {J Physiol},

volume = {599},

number = {24},

pages = {5397--5416},

abstract = {DFNA25 is an autosomal-dominant and progressive form of human deafness caused by mutations in the SLC17A8 gene, which encodes the vesicular glutamate transporter type 3 (VGLUT3). To resolve the mechanisms underlying DFNA25, we studied phenotypes of mice harbouring the p.A221V mutation in humans (corresponding to p.A224V in mice). Using auditory brainstem response and distortion product otoacoustic emissions, we showed progressive hearing loss with intact cochlear amplification in the VGLUT3 mouse. The summating potential was reduced, indicating the alteration of inner hair cell (IHC) receptor potential. Scanning electron microscopy examinations demonstrated the collapse of stereocilia bundles in IHCs, leaving those from outer hair cells unaffected. In addition, IHC ribbon synapses underwent structural and functional modifications at later stages. Using super-resolution microscopy, we observed oversized synaptic ribbons and patch-clamp membrane capacitance measurements showed an increase in the rate of the sustained releasable pool exocytosis. These results suggest that DFNA25 stems from a failure in the mechano-transduction followed by a change in synaptic transfer. The VGLUT3 mouse model opens the way to a deeper understanding and to a potential treatment for DFNA25. KEY POINTS: The vesicular glutamate transporter type 3 (VGLUT3) loads glutamate into the synaptic vesicles of auditory sensory cells, the inner hair cells (IHCs). The VGLUT3-p.A211V variant is associated with human deafness DFNA25. Mutant mice carrying the VGLUT3-p.A211V variant show progressive hearing loss. IHCs from mutant mice harbour distorted stereocilary bundles, which detect incoming sound stimulation, followed by oversized synaptic ribbons, which release glutamate onto the afferent nerve fibres. These results suggest that DFNA25 stems from the failure of auditory sensory cells to faithfully transduce acoustic cues into neural messages.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33775453,

title = {Leveraging VGLUT3 Functions to Untangle Brain Dysfunctions},

author = {Mathieu Favier and Nicolas Pietrancosta and Salah El Mestikawy and Giuseppe Gangarossa},

doi = {10.1016/j.tips.2021.03.003},

issn = {1873-3735},

year  = {2021},

date = {2021-06-01},

journal = {Trends Pharmacol Sci},

volume = {42},

number = {6},

pages = {475--490},

abstract = {Vesicular glutamate transporters (VGLUTs) were long thought to be specific markers of glutamatergic excitatory transmission. The discovery, two decades ago, of the atypical VGLUT3 has thoroughly modified this oversimplified view. VGLUT3 is strategically expressed in discrete populations of glutamatergic, cholinergic, serotonergic, and even GABAergic neurons. Recent reports show the subtle, but critical, implications of VGLUT3-dependent glutamate co-transmission and its roles in the regulation of diverse brain functions and dysfunctions. Progress in the neuropharmacology of VGLUT3 could lead to decisive breakthroughs in the treatment of Parkinson's disease (PD), addiction, eating disorders, anxiety, presbycusis, or pain. This review summarizes recent findings on VGLUT3 and its vesicular underpinnings as well as on possible ways to target this atypical transporter for future therapeutic strategies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32559027,

title = {Metabotropic glutamate type 5 receptor binding availability during dextroamphetamine sensitization in mice and humans},

author = {Kelly Smart and Atsuko Nagano-Saito and Michele S Milella and Diana Yae Sakae and Mathieu Favier and Erika Vigneault and Leanne Louie and Alison Hamilton and Stephen S G Ferguson and Pedro Rosa-Neto and Sridar Narayanan and Salah El Mestikawy and Marco Leyton and Chawki Benkelfat},

doi = {10.1503/jpn.190162},

issn = {1488-2434},

year  = {2021},

date = {2021-01-01},

journal = {J Psychiatry Neurosci},

volume = {46},

number = {1},

pages = {E1--E13},

abstract = {BACKGROUND: Glutamate transmission is implicated in drug-induced behavioural sensitization and the associated long-lasting increases in mesolimbic output. Metabotropic glutamate type 5 (mGlu5) receptors might be particularly important, but most details are poorly understood.nnMETHODS: We first assessed in mice (n = 51, all male) the effects of repeated dextroamphetamine administration (2.0 mg/kg, i.p.) on locomotor activity and binding of the mGlu5 ligand [3H]ABP688. In a parallel study, in 19 stimulant-drug-naïve healthy human volunteers (14 female) we administered 3 doses of dextroamphetamine (0.3 mg/kg, p.o.) or placebo, followed by a fourth dose 2 weeks later. We measured [11C]ABP688 binding using positron emission tomography before and after the induction phase. We assessed psychomotor and behavioural sensitization using speech rate, eye blink rate and self-report. We measured the localization of mGlu5 relative to synaptic markers in mouse striatum using immunofluorescence.nnRESULTS: We observed amphetamine-induced psychomotor sensitization in mice and humans. We did not see group differences in mGlu5 availability following 3 pre-challenge amphetamine doses, but group differences did develop in mice administered 5 doses. In mice and humans, individual differences in mGlu5 binding after repeated amphetamine administration were negatively correlated with the extent of behavioural sensitization. In drug-naïve mice, mGlu5 was expressed at 67% of excitatory synapses on dendrites of striatal medium spiny neur.nnLIMITATIONS: Correlational results should be interpreted as suggestive because of the limited sample size. We did not assess sex differences.nnCONCLUSION: Together, these results suggest that changes in mGlu5 availability are not part of the earliest neural adaptations in stimulant-induced behavioural sensitization, but low mGlu5 binding might identify a higher propensity for sensitization.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33164988,

title = {Cholinergic dysfunction in the dorsal striatum promotes habit formation and maladaptive eating},

author = {Mathieu Favier and Helena Janickova and Damian Justo and Ornela Kljakic and Léonie Runtz and Joman Y Natsheh and Tharick A Pascoal and Jurgen Germann and Daniel Gallino and Jun-Ii Kang and Xiang Qi Meng and Christina Antinora and Sanda Raulic and Jacob Pr Jacobsen and Luc Moquin and Erika Vigneault and Alain Gratton and Marc G Caron and Philibert Duriez and Mark P Brandon and Pedro Rosa Neto and M Mallar Chakravarty and Mohammad M Herzallah and Philip Gorwood and Marco Am Prado and Vania F Prado and Salah El Mestikawy},

doi = {10.1172/JCI138532},

issn = {1558-8238},

year  = {2020},

date = {2020-12-01},

journal = {J Clin Invest},

volume = {130},

number = {12},

pages = {6616--6630},

abstract = {Dysregulation of habit formation has been recently proposed as pivotal to eating disorders. Here, we report that a subset of patients suffering from restrictive anorexia nervosa have enhanced habit formation compared with healthy controls. Habit formation is modulated by striatal cholinergic interneurons. These interneurons express vesicular transporters for acetylcholine (VAChT) and glutamate (VGLUT3) and use acetylcholine/glutamate cotransmission to regulate striatal functions. Using mice with genetically silenced VAChT (VAChT conditional KO, VAChTcKO) or VGLUT3 (VGLUT3cKO), we investigated the roles that acetylcholine and glutamate released by cholinergic interneurons play in habit formation and maladaptive eating. Silencing glutamate favored goal-directed behaviors and had no impact on eating behavior. In contrast, VAChTcKO mice were more prone to habits and maladaptive eating. Specific deletion of VAChT in the dorsomedial striatum of adult mice was sufficient to phenocopy maladaptive eating behaviors of VAChTcKO mice. Interestingly, VAChTcKO mice had reduced dopamine release in the dorsomedial striatum but not in the dorsolateral striatum. The dysfunctional eating behavior of VAChTcKO mice was alleviated by donepezil and by l-DOPA, confirming an acetylcholine/dopamine deficit. Our study reveals that loss of acetylcholine leads to a dopamine imbalance in striatal compartments, thereby promoting habits and vulnerability to maladaptive eating in mice.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32873747,

title = {Targeting Vesicular Glutamate Transporter Machinery: Implications on Metabotropic Glutamate Receptor 5 Signaling and Behavior},

author = {Karim S Ibrahim and Khaled S Abd-Elrahman and Salah El Mestikawy and Stephen S G Ferguson},

doi = {10.1124/molpharm.120.000089},

issn = {1521-0111},

year  = {2020},

date = {2020-10-01},

journal = {Mol Pharmacol},

volume = {98},

number = {4},

pages = {314--327},

abstract = {Cross talk between both pre- and postsynaptic components of glutamatergic neurotransmission plays a crucial role in orchestrating a multitude of brain functions, including synaptic plasticity and motor planning. Metabotropic glutamate receptor (mGluR) 5 exhibits promising therapeutic potential for many neurodevelopmental and neurodegenerative disorders as a consequence of its modulatory control over diverse neuronal networks required for memory, motor coordination, neuronal survival, and differentiation. Given these crucial roles, mGluR5 signaling is under the tight control of glutamate release machinery mediated through vesicular glutamate transporters (VGLUTs) that ultimately dictate glutamatergic output. A particular VGLUT isoform, VGLUT3, exhibits an overlapping, but unique, distribution with mGluR5, and the dynamic cross talk between mGluR5 and VGLUT3 is key for the function of specific neuronal networks involved in motor coordination, emotions, and cognition. Thus, aberrant signaling of the VGLUT3-mGluR5 axis is linked to various pathologies including, but not limited to, Parkinson disease, anxiety disorders, and drug addiction. We argue that a comprehensive profiling of how coordinated VGLUT3-mGluR5 signaling influences overall glutamatergic neurotransmission is warranted. SIGNIFICANCE STATEMENT: Vesicular glutamate receptor (VGLUT) 3 machinery orchestrates glutamate release, and its distribution overlaps with metabotropic glutamate receptor (mGluR) 5 in regional brain circuitries, including striatum, hippocampus, and raphe nucleus. Therefore, VGLUT3-mGluR5 cross talk can significantly influence both physiologic and pathophysiologic glutamatergic neurotransmission. Pathological signaling of the VGLUT3-mGluR5 axis is linked to Parkinson disease, anxiety disorders, and drug addiction. However, it is also predicted to contribute to other motor and cognitive disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}