Contribution of Vesicular Glutamate Transporters to Stress Response and Related Psychopathologies: Studies in VGluT3 Knockout Mice

Horváth, Hanga Réka; Fazekas, Csilla Lea; Balázsfi, Diána; Jain, S. K.; Haller, József; Zelena, Dóra

doi:10.1007/s10571-017-0528-7

Cited by 11 publications

(16 citation statements)

References 134 publications

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“…The three subtypes discovered so far (VGluT1, 2, and 3) show complementary localization throughout the brain. The dominant isoform in the cortex is VGluT1, VGluT2 in the brainstem, while VGluT3 is expressed in certain subcortical nuclei [79].…”

Section: Excitation: Glutamatementioning

confidence: 99%

Stress Adaptation and the Brainstem with Focus on Corticotropin-Releasing Hormone

Chaves

Fazekas

Horváth

et al. 2021

IJMS

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Stress adaptation is of utmost importance for the maintenance of homeostasis and, therefore, of life itself. The prevalence of stress-related disorders is increasing, emphasizing the importance of exploratory research on stress adaptation. Two major regulatory pathways exist: the hypothalamic–pituitary–adrenocortical axis and the sympathetic adrenomedullary axis. They act in unison, ensured by the enormous bidirectional connection between their centers, the paraventricular nucleus of the hypothalamus (PVN), and the brainstem monoaminergic cell groups, respectively. PVN and especially their corticotropin-releasing hormone (CRH) producing neurons are considered to be the centrum of stress regulation. However, the brainstem seems to be equally important. Therefore, we aimed to summarize the present knowledge on the role of classical neurotransmitters of the brainstem (GABA, glutamate as well as serotonin, noradrenaline, adrenaline, and dopamine) in stress adaptation. Neuropeptides, including CRH, might be co-localized in the brainstem nuclei. Here we focused on CRH as its role in stress regulation is well-known and widely accepted and other CRH neurons scattered along the brain may also complement the function of the PVN. Although CRH-positive cells are present on some parts of the brainstem, sometimes even in comparable amounts as in the PVN, not much is known about their contribution to stress adaptation. Based on the role of the Barrington’s nucleus in micturition and the inferior olivary complex in the regulation of fine motoric—as the main CRH-containing brainstem areas—we might assume that these areas regulate stress-induced urination and locomotion, respectively. Further studies are necessary for the field.

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Section: Excitation: Glutamatementioning

confidence: 99%

Stress Adaptation and the Brainstem with Focus on Corticotropin-Releasing Hormone

Chaves

Fazekas

Horváth

et al. 2021

IJMS

Self Cite

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“…In fact, VGLUT3 −/− mice that are hyperactive when placed in normal housing conditions, turn out to be hypoactive when exposed to stressful environments. 9,43,44 Within each strain, VGLUT3 expression varies substantially according to the brain region involved in anxiety-and drug-related behavior. Between strains, the overall VGLUT3 expression is also different, with C3H/HeH = 129/Sv, C57Bl/6N and BALB/c = DBA/2, from the highest VGLUT3 expression to the lowest, respectively.…”

Section: Discussionmentioning

confidence: 99%

Differential expression of VGLUT3 in laboratory mouse strains: Impact on drug‐induced hyperlocomotion and anxiety‐related behaviors

Sakae

Ramet

Henrion

et al. 2018

Genes Brain and Behavior

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The atypical vesicular glutamate transporter VGLUT3 is present in subpopulations of GABAergic interneurons in the cortex and the hippocampus, in subgroups of serotoninergic neurons in raphe nuclei, and in cholinergic interneurons in the striatum. C56BL/6N mice that no longer express VGLUT3 (VGLUT3−/−) display anxiety‐associated phenotype, increased spontaneous and cocaine‐induced locomotor activity and decreased haloperidol‐induced catalepsy. Inbred mouse strains differ markedly in their sensitivity to anxiety and behavioral responses elicited by drugs. The purpose of this study was to investigate strain differences in VGLUT3 expression levels and its potential correlates with anxiety and reward‐guided behaviors. Five inbred mouse lines were chosen according to their contrasted anxiety and drugs sensitivity: C57BL/6N, C3H/HeN, DBA/2J, 129/Sv, and BALB/c. VGLUT3 protein expression was measured in different brain areas involved in reward or mood regulation (such as the striatum, the hippocampus, and raphe nuclei) and genetic variations in Slc17a8, the gene encoding for VGLUT3, have been explored. These five inbred mouse strains express very different levels of VGLUT3, which cannot be attributed to the genetic variation of the Slc17a8 locus. Furthermore, mice behavior in the open field, elevated plus maze, spontaneous‐ and cocaine‐induced locomotor was highly heterogeneous and only partially correlated to VGLUT3 levels. These data highlight the fact that one single gene polymorphism could not account for VGLUT3 expression variations, and that region specific VGLUT3 expression level variations might play a key role in the modulation of discrete behaviors.

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“…Under physiological conditions, raphe/amygdala neuronal pathway regulate stress response mechanisms via hypothalamicpituitary-adrenal (HPA) axis (Pompili et al, 2010). Loss of VGLUT3 signaling elevates HPA axis activity in mice and contributes to the development of anxious phenotype (Horváth et al, 2018).…”

Section: Anxiety Disordersmentioning

confidence: 99%

Targeting VGLUT Machinery: Implications on mGluR5 Signaling and Behavior

et al. 2020

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Crosstalk between both pre-and post-synaptic components of glutamatergic neurotransmission plays a crucial role in orchestrating a multitude of brain functions including synaptic plasticity and motor planning. Metabotropic glutamate receptor 5 (mGluR5) exhibits a promising therapeutic potential for many neurodevelopmental and neurodegenerative disorders, as the 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) to ultimately dictate glutamatergic output. A particular VGLUT isoform, VGLUT3, exhibits an overlapping, but unique, distribution with mGluR5 and the dynamic crosstalk 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's 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 3 (VGLUT3) machinery orchestrates glutamate release and its distribution overlaps with metabotropic glutamate receptor 5 (mGluR5) in regional brain circuitries including striatum, hippocampus and raphe nucleus. Therefore, VGLUT3/mGluR5 crosstalk can significantly influences both physiological and pathophysiological glutamatergic neurotransmission. Pathological signaling of the VGLUT3/mGluR5 axis is linked to Parkinson's disease, anxiety disorders and drug addiction. However, it is also predicted to contribute to other motor and cognitive disorders.

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Contribution of Vesicular Glutamate Transporters to Stress Response and Related Psychopathologies: Studies in VGluT3 Knockout Mice

Cited by 11 publications

References 134 publications

Stress Adaptation and the Brainstem with Focus on Corticotropin-Releasing Hormone

Stress Adaptation and the Brainstem with Focus on Corticotropin-Releasing Hormone

Differential expression of VGLUT3 in laboratory mouse strains: Impact on drug‐induced hyperlocomotion and anxiety‐related behaviors

Targeting VGLUT Machinery: Implications on mGluR5 Signaling and Behavior

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