Biology subjects

El Mestikawy, S.

Publications and source records attributed to El Mestikawy, S..

6 recordsLinked to original sources

bioRxiv2026

The VGLUT3-p.T8I Mutation Alters Striatal Acetylcholine Dynamics in Response to Social Stressors and Drives Selective Social Avoidance in Male Mice

The nucleus accumbens (NAc) is a key structure translating dopaminergic inputs into social avoidance following repeated social defeat. Within the NAc, dopamine (DA) release is modulated in part by cholinergic interneurons (CINs). CINs express the vesicular glutamate transporter type 3 (VGLUT3), which supports glutamate co-release and regulates vesicular acetylcholine (ACh) loading, thereby fine-tuning cholinergic signaling. A rare human VGLUT3-p.T8I missense variant is associated with compulsive behaviors toward food and drugs of abuse. We hypothesized that p.T8I disrupts NAc ACh dynamics and affects social avoidance following social defeat. Male and female mice expressing the VGLUT3-p.T8I variant were exposed to a 10-day chronic social defeat stress (CSDS) paradigm. Social avoidance toward the aggressor strain and a C57BL/6 (B6) conspecific was measured using the social interaction and 3-chamber tests, and anxiety-like behavior was evaluated in the elevated zero maze. Fiber photometry was used to monitor ACh and DA dynamics in the NAc medial shell (NAcMsh) during CSDS and social interaction. After CSDS, VGLUT3T8I/T8I males showed aggressor strain-specific social avoidance and increased anxiety-like behavior compared to WT mice. Mutants showed blunted CSDS-induced ACh increase during attacks but enhanced ACh release upon re-exposure to the CD1 aggressor strain correlating with avoidance severity. DA dynamics were minimally affected. Females, regardless of genotype, displayed a male-mutant-like phenotype. In males, the VGLUT3-p.T8I variant alters NAcMsh ACh signaling and promotes selective social avoidance toward aggressors and elevated anxiety after CSDS, highlighting a potential cholinergic mechanism underlying stress-induced social avoidance with broader relevance to psychiatric disorders.

neuroscience↗

bioRxiv2024

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

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-immunorective 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. Most glutamatergic synaptic terminals formed type-1 synapses and some were positive for CB1 receptor concentrated in the presynaptic active zone, unlike 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.

neuroscience↗

bioRxiv2023

Evidence for a role of 5-HT-glutamate co-releasing neurons in acute stress mechanisms

The majority of midbrain 5-hydroxytryptamine (5-HT) neurons express the vesicular glutamate transporter 3 (VGLUT3) and co-release 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 immunocytochemistry and conditional gene knock out in mice to test the hypothesis that glutamate co-releasing 5-HT neurons would be 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 localised 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 behaviour, a measure of active coping. Wildtype mice also showed increased climbing when administered fluoxetine, revealing an interesting parallel between the behavioural 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 released at the 5-HT synapse may impact on stress susceptibility.

neuroscience↗

bioRxiv2023

Persistent Extrasynaptic Hyperdopaminergia in the mouse Hippocampus Induces Plasticity and Recognition Memory Deficits Reversed by Antipsychotics

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.

neuroscience↗

bioRxiv2020

VGLUT3-p.A211V variant fuses stereocilia bundle and elongates synaptic ribbons in the human deafness DFNA25

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 the phenotype of the mouse harboring the p.A221V mutation in human (corresponding to p.A224V in mouse). Using auditory brainstem response and distortion products of otoacoustic emissions, we showed that VGLUT3A224V/A224V mouse replicates the DFNA25 progressive hearing loss with intact cochlear amplification. Scanning electron microscopy examinations demonstrated fused stereocilia bundle of the inner hair cells (IHCs) as the primary cause for DFNA25. In addition, the IHC ribbon synapses undergo structural and functional modifications at later stages. Using super-resolution microscopy, we observed oversized synaptic ribbons associated with an increase in the rate of the sustained releasable pool of exocytosis. These results indicate that the primary defect in DFNA25 stems from a failure in the mechano-transduction followed by a change in synaptic transfer. The VGLUT3A224V/A224V mouse model opens the way to a deeper understanding and to a potential treatment of DFNA25.

neuroscience↗

bioRxiv2018

Mammalian vesicular glutamate transporter VGLUT1 reduces synaptic vesicle superpool size and spontaneous release frequency.

Glutamate secretion at excitatory synapses is tightly regulated to allow for the precise tuning of synaptic strength. Vesicular Glutamate Transporters (VGLUT) accumulate glutamate into synaptic vesicles (SV) and thereby regulate quantal size. Further, the number of release sites and the release probability of SVs maybe regulated by the organization of active zone proteins and SV clusters. In the present work, we uncover a mechanism mediating an increased SV clustering through a tripartite interaction of VGLUT1, endophilinA1 and intersectin1. This strengthening of SV clusters results in a combined reduction of axonal SV super-pool size and miniature excitatory events frequency. Our findings support a model in which clustered vesicles are held together through multiple weak interactions between SH3 domains and proline rich sequences of synaptic proteins. In mammals, VGLUT1 gained a poly-proline sequence that recruits endophilinA1 and turns the transporter into a dual regulator of quantal release parameters at excitatory synapses.

neuroscience↗