VGLUT3+ Neurons in Hippocampal Activity and Behaviour: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Dean Liu and Version 1 by Dóra Zelena.

Neurons using glutamate as a neurotransmitter can be characterised by vesicular glutamate transporters (VGLUTs). Among the three subtypes, VGLUT3 is often co-localise with other “classical” neurotransmitters and can modulate their release. Its contribution to sensory processes (including seeing, hearing, and mechanosensation) is well characterised. However, its involvement in learning and memory can only be assumed based on its prominent hippocampal presence. Beside local VGLUT3 positive network hippocampus gets innervation from the median raphe. This hippocampal glutamatergic network plays a pivotal role in several important processes (e.g., learning and memory, emotions, epilepsy, cardiovascular regulation). 

  • vesicular glutamate transporter
  • hippocampus
  • sensory processes
  • learning and memory
  • emotions

1. Introduction

In the central nervous system (CNS), neurons are classified based on the neurotransmitters they express. While Dale’s principle originally stated that one neuron utilises one neurotransmitter, wresearchers now know that a cell can express multiple different molecules to communicate [1]. However, even today, it is still regarded such that neurons have one main “classical” neurotransmitter type (e.g., excitatory glutamate (Glu) or inhibitory gamma aminobutyric acid (GABA)) and express numerous other secondary ones, mainly peptides. As these “classical” neurotransmitters are small molecules, they are often intermediates of the metabolism and thus detectable in all cells. Therefore, neuron classification is based mainly on the transporter proteins that pack the neurotransmitters into vesicles, from which the molecules are later released into the synaptic cleft [2]. One of the most abundant types of neurons in the CNS is the glutamatergic cells, which exert excitation in most cases via the release of Glu. Two distinct protein families transport Glu through membranes: the excitatory amino acid transporters (EAATs) and the vesicular glutamate transporters (VGLUTs). EAATs, being responsible for the termination of the synaptic signal, can be found in the plasma membrane of pre- and postsynaptic neurons, as well as in glial cells, and thus cannot be used to characterise glutamatergic neurons [3].
On the contrary, VGLUTs are expressed on neuronal synaptic vesicles’ membrane and thought to be characteristic to neurons only. They belong to the solute carrier family 17, which is a sodium-dependent phosphate transporter family. To maintain balance of charge, pH, and ions, glutamatergic synaptic vesicle membranes contain V-ATPases (proton pumps) as well, which establish acidic pH inside the vesicles. VGLUTs themselves carry not only Glu in its anionic form but also require Cl− and a cation (preferably H+ or K+) to work [4,5,6][4][5][6]. According to Preobraschenski’s model, in the first conformation state, VGLUTs bind a Glu− and a K+ molecule from the lumen, while a Cl− ion is constantly bound due to the high affinity [4]. After changing conformation, in the second state, the transporter lets go of the Glu− and K+ inside and instead gains high affinity to Cl− and H+, which are transported to the cytosol to restart the cycle.

2. Characterisation of VGLUT3

2.1. Anatomical Distribution of VGLUT3 in the Central Nervous System

The DNA sequence of VGLUT3 is over 70% identical to the other isoforms, and it utilises the same molecular mechanism to load vesicles with Glu [5,6,8,16,17][5][6][7][8][9]. Moreover, its presence is enough to induce the glutamatergic phenotype, as Glu release was detected in GABAergic striatal primary cultures infected with VGLUT3-expressing lentivirus. After 14 days, Glu release-induced EPSCs were detected in the infected cells, whereas no activation was observed in the control GABAergic cells [8][7].
However, VGLUT3 also shows numerous distinctive characteristics. Firstly, its anatomical distribution is unique: while VGLUT1 and 2 show complementary localisation, VGLUT3 appears intermingled with other transporters, appearing mainly, but not exclusively in subcortical structures. On the mRNA level, it has been shown in neurons of the cortex (layers II, III, and VI), caude putamen, amygdala, hippocampus, hypothalamus, nucleus accumbens, habenula, bed nucleus of stria terminalis (BNST), striatum, ventral tegmental area (VTA), substantia nigra pars compacta, and midbrain raphe nuclei [5[5][6][10][11][8][12][13][14][15][16],6,11,13,16,18,19,20,21,22], with controversial results in the cerebellum (in the granular layer, molecular layer, Purkinje cells reported in [5], but not found by others [11,16][10][8]).
Immunohistochemistry on protein level strengthened the mRNA findings: cortical neurons indeed express VGLUT3 alongside the mRNA [20][14]. Inhibitory interneurons and pyramidal cells expressing VGLUT3 proteins are also present in layers II and III of the cortex as well as boutons, representing VGLUT3+ synapses in layers II, III, V, and VI [23][17]. In the hippocampus, pyramidal cell bodies and their dendrites are innervated by VGLUT3+ synapses, while the stratum radiatum somas were also VGLUT3-positive [5,6,11,16][5][6][10][8]. Similar results were shown in the neurons of olfactory bulb, caudoputamen, nucleus accumbens, striatum, hypothalamus, VTA, substantia nigra pars compacta, and raphe nuclei [5,6,13,16,24,25,26,27][5][6][11][8][18][19][20][21]. Moreover, VGLUT3 is not exclusively expressed in the nerve terminals or cell bodies but can also be found in dendrites [5,13][5][11]. Interestingly, astrocytes [5,28][5][22] and ependymal cell [13,16][11][8] were also VGLUT3 positive; however, in situ hybridization did not confirm this on the mRNA level [6,19,29][6][13][23].
VGLUT3 is also detectable in the spinal cord. Numerous VGLUT3+ axon terminals can be found in its intermediolateral cell column, where they form both excitatory (asymmetric) and inhibitory (symmetric) synapses, putatively having a role in thermoregulation [22,30,31][16][24][25]. The retrotrapezoid nucleus, responsible for chemoreception, is also innervated by VGLUT3+ projections [32][26]. However, VGLUT3 mRNA-positive somas were not detected in the spinal cord [31][25]. Interestingly, in rat, pulpal blood flow was regulated by VGLUT3+ nerve terminals [33][27], suggesting the possibility of an even more peripheral projection. Moreover, VGLUT3 immunoreactivity was detected in the heart, liver, and kidney but not in intestinal or lung tissue [34][28]. However, a specific VGLUT3 isoform is characteristic to the CNS.

2.2. Glutamate as a Secondary Neurotransmitter in VGLUT3+ Neurons

Another interesting characteristic of the VGLUT3 is the fact it is co-expressed with other molecules that are considered as traditional main neurotransmitters. Controversially, less is known about VGLUT3 co-expression with non-classical, peptide neurotransmitters.
VGLUT3 is often found in symmetric, thus, inhibitory nerve terminals, especially in the hippocampus and the cortex [5,16,20,21,35][5][8][14][15][29]. A small portion of cortical GABAergic interneurons that are projecting locally are VGLUT3 positive, and they also co-express neurokinin B and cholecystokinin (CCK) markers. These neurons form basket-like arborisations around other, putatively neurokinin B positive interneurons [20][14]. In the hippocampus, glutamate decarboxylase positive (GAD+), GABAergic neurons also express VGLUT3, indicating that inhibitory interneurons also release Glu [5,35,36,37][5][29][30][31].
Around ≈7% of the GABAergic neurons in the BNST are positive for VGLUT3 mRNA, and part of them project to the VTA [21,38][15][32]. In the basal nucleus of the amygdala, a subset of CCK+ GABAergic interneurons also express VGLUT3, along with cannabinoid receptor type 1 (CB1R) in their axon terminals [27,39][21][33]. Interestingly, these neurons show little electrophysiological and no morphological differences compared to their calbindin positive counterparts [27][21], but they form an interesting invagination type of synapse into the cell bodies of pyramidal neurons [39][33].
In the striatum, virtually all cholinergic cells co-express the vesicular acetylcholine transporter (VAChT) and VGLUT3 [5,6,16][5][6][8]. In the basal forebrain (horizontal diagonal band of Broca), cholinergic neurons also co-express VGLUT3, however, in a more restricted way [18,35,40,41][12][29][34][35]. Some of these cells project to the internal plexiform layer of the main olfactory bulb, although electrophysiological measurements showed that postsynaptic currents are derived from nicotinic and GABAergic activation rather than glutamatergic [40][34]. Other cells from the basal forebrain project to the basolateral amygdala and express both choline acetyltransferase (ChAT) and VGLUT3 [41][35]. Interestingly, in the amygdala, some CCK and CB1R-positive interneurons also express VGLUT3 [27][21]. In the striatum, VGLUT3 plays a crucial role in the vesicular loading of ACh [42,43][36][37] and excites local fast-spiking interneurons via both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) (both are ionotropic glutamatergic) receptors. It is thought that this co-release of Glu and ACh plays a role in the regulation of locomotor activity [44][38]. Similar results were found in basal forebrain nuclei such as the medial septum, diagonal bands, and nucleus basalis [18][12].
Midbrain raphe nuclei are mostly known for their 5-HT content, which is marked by serotonin transporters (SERT). Interestingly, in these cell groups, SERT+ and VGLUT3+ markers are often co-expressed, but they can also be found separately [5,16,19,20,45,46,47,48,49,50][5][8][13][14][39][40][41][42][43][44]. Terminals originating from serotonergic neurons often co-express VGLUT3 in the cortex, especially in layers II/III [20][14]. The source of these terminals is mainly in the dorsal raphe (DR) [19[13][41][43][44][45][46],47,49,50,51,52], which also projects to the striatum [49][43]. Interestingly, these axons form varicosities that are morphologically larger than others [49][43]. Other projections in the VTA and nucleus accumbens play a role in reward signalling [52,53,54][46][47][48]. In VTA, both 5-HT and Glu originating from VGLUT3+ axon terminals are released, contributing to social stress susceptibility: their inhibition facilitated social avoidance after subthreshold social defeat stress [53][47]. However, it is unknown whether the VGLUT3+ subpopulation plays a role in this. In another study, it was shown that the VGLUT3+/5-HT+ DR projections to VTA dopaminergic neurons were excitatory and induced DA release in the nucleus accumbens, positively driving conditioned place preference [54][48]. Similarly, 5-HT and VGLUT3 co-localisation was detected in the DR-basal amygdala projections, possibly contributing to fear memory [55][49]. In the basal amygdala, the axon terminals either release 5-HT or Glu based on the frequency of firing [56][50]. Other than these areas, DR VGLUT3+ neurons also project to the substantia nigra pars compacta, different thalamic and hypothalamic nuclei, where they do not necessarily co-express 5-HT, and their somatas are mainly located in the shell region of the DR [19][13]. Additionally, there is a subset of VGLUT3+ cells in the superior colliculus that also project to substantia nigra pars compacta and form asymmetric and thus excitatory synapses on local dopaminergic neurons [57][51].
In another known serotonergic nucleus, the median raphe (MR), Glu released from VGLUT3+ vesicles can be the main neurotransmitter, but it can also be found in serotonergic as well as—in small percentage—in GABAergic neurons [19,23,58][13][17][52]. Interestingly, primary raphe cell cultures from VGLUT3 KO mice show vulnerability and are less likely to survive in vitro compared to cells isolated from wild-type animals [46][40]. However, there seems to be topological heterogeneity in the neurochemical characteristics of differently projecting serotonergic and VGLUT3+ axon varicosities. For example, in the cortex, hippocampus, nucleus accumbens, and striatum, most varicosities expressed both SERT and VGLUT3 markers [49,59][43][53]. On the other hand, Voisin et al. [46][40] showed the opposite results: in the septum, striatum, and hippocampus, these two markers were barely co-expressed in the same varicosities. Similarly, in the hippocampus, second rhombomere (R2)-derived, Pet1+ (transcription factor known to represent serotonergic cells [60][54]) boutons were mostly VGLUT3+ but not 5-HT+ [61][55]. However, serotonergic neurons originating from other rhombomeres co-expressed VGLUT3+ and 5-HT in their terminals. As of now, it is unknown whether this is a technical difference (antibody, different animal strains) or physiologically important observation related to functionality. It is important to note that while this segregation (i.e., 5-HT+, GLUT3+, or co-expressed) in MR-hippocampus projections was confirmed [62][56], it was also highlighted that VGLUT3 may be co-expressed in vesicular monoamine transporter 2 positive (VMAT2+) and 5-HT+ terminals even if they were negative for the SERT marker. As of now, it is believed that this co-expression facilitates the vesicular filling of the main neurotransmitter (so-called vesicular synergy) [42,62,63][36][56][57]. However, in the case of GABAergic co-expression, both pro [64][58] and contra [65,66][59][60] arguments have been published, leaving the question open. A most probable explanation is that the same projection may have different subtypes based upon their co-expression profile, and different authors found different populations in their samples by chance. The co-expression of “classical” neurotransmitters may be further coloured by an array of peptide co-transmitters [67,68][61][62].
Similar to the midbrain raphe nuclei, VGLUT3 can be found alone or co-expressed in a subset of putatively GABAergic and/or aminergic cells in the medullary raphe nuclei, such as the raphe pallidus, raphe magnus, raphe obscurus, and parapyramidal area. They send projections to the spinal cord (see earlier) [22,30][16][24]. It has also been suggested that VGLUT3 is also co-expressed with VGLUT1 and 2, but this seems to be brain area [17][9] and species specific (might be different even between rats and mice) [17,69][9][63].
Interestingly, VGLUT3 has the ability to signal retrogradely [5,70][5][64]. Crepel et al. showed that cerebellar principle cells utilise Glu released from VGLUT3 containing vesicles to retrogradely signal and regulate incoming signals. In the cortex, VGLUT3 is also present in the dendrites of layer II principal cells and may negatively control the input from local interneurons [24][18].

2.3. Electrophysiological Characteristics of VGLUT3

Lentiviruses containing the sequences of the three VGLUT isoforms were used in primary autopathic cultures from VGLUT1 KO hippocampal and VGLUT2 KO thalamic tissue for direct comparison. All three types of VGLUT expression rescued the deficit in EPSC peaks and charges and showed no significant differences from hippocampal VGLUT1 wild-type (WT) neurons or from each other. Thus, it was concluded that all 3 isoforms perform the basic function in a similar manner. However, compared to WT VGLUT1+ and lentiviral-rescued VGLUT1 cells, VGLUT2 and VGLUT3-expressing neurons showed significantly greater release probability indicated by increased paired-pulse depression [8][7].
Table 1 shows some representative VGLUT3+ neuron populations in comparison to general GABAergic interneurons and their electrophysiological characteristics. Even though they are located anatomically differently, their major characteristics do not vary in great length.
Table 1. Electrophysiological characteristics of different VGLUT3 containing and non-containing interneurons in the central nervous system.
  GABAergic Interneurons in the Cortex GABAergic Interneurons in the Hippocampus VGLUT3+ Interneurons in the Amygdala VGLUT3+ Interneurons in the Hippocampus
Resting membrane potential −57.48–−49.40 mV NA NA −59.00–−56.90 mV
Input resistance 219.77–419.61 MΩ 107.89 MΩ 168.10 MΩ 149.70–158.50 MΩ
Action potential threshold −32.67–−27.82 mV −42.81 mV −38.80 mV −41.90–−39.86 mV
Action potential amplitude 71.30–86.11 mV 74.27 mV 71.60 mV 55.70–57.40 mV
Firing frequency 19.34–52.48 Hz (2×) 15.00 Hz

(steady trace)		 31.50 Hz

(2×)		 31.30–34.90 Hz (2×)
Amplitude of after-hyperpolarisation 8.60–17.63 mV 12.68 mV

(new method)		 14.70 mV −11.80–−10.30 mV
Co-transmitters CCK CCK CCK, GABA CCK, GABA
Reference [71], all subtypes displayed[65], all subtypes displayed [72][66] [27][21] [65], both subtypes displayed[59], both subtypes displayed
The expression of VGLUT3 does not change the main properties of the interneurons. For detailed information and results, please refer to each original research article. CCK: cholecystokinin; NA: not available; VGLUT3: vesicular glutamate transporter type 3.

3. Implications of VGLUT3 in Physiology

As a recently discovered protein, the exact role of VGLUT3 is not completely understood. Scarce information are available both from the CNS and the periphery.
First of all, VGLUT3 is highly implicated in sensory processes. In the retina, VGLUT3 plays a crucial role in the physiology of a new subtype of putatively excitatory amacrine cells [5,16,34,73][5][8][28][67]. VGLUT3 is also expressed in the inner hair cells and spiral ganglion cells of the cochlea [74,75,76][68][69][70] as well as in the inhibitory sound-localisation pathway [77][71]. They are needed for auditory coding, as without properly functioning proteins, the stereocilary bundle structure and synaptic organisation was lost [78][72]. As a result, VGLUT3 KO mice are deaf [76,79,80][70][73][74]. VGLUT3-mediated glutamatergic neurotransmission is also responsible for noise-induced threshold shifts [81][75]. Lastly, low threshold mechanosensitive cells in the hairy skin that project to the dorsal horn of the spinal cord with C-type fibres also utilise VGLUT3 to signal pleasant touch information [69,82,83][63][76][77]. However, unpleasant sensory information of an electric foot-shock was not influenced by the lack of VGLUT3 in KO mice [84][78].
The participation of VGLUT3 in endocrine regulation was confirmed by several studies. Firstly, glutamate may influence the stress response at several points [85][79], and VGLUT3 might be especially involved in catecholaminergic regulation, as around 25% of the chromaffin cells in the adrenal medulla also express VGLUT3 [86][80]. The expression of the hypothalamic regulator of the so-called stress axis (hypothalamic–pituitary adrenocortical axis, HPA), the corticotropin-releasing hormone (CRH) was increased in VGLUT3 KO mice and the stressor-induced corticosterone (end-hormone of the HPA axis) elevation was higher in them compared to their WT littermates [84,85,87][78][79][81]. However, wresearchers might assume that the role of VGLUT3 might be on remote brain areas influencing the perception/interpretation of the stressor rather than a direct effect on the HPA axis as its presence (both in the somas as well as in afferent fibres) was not confirmed so far on its elements. Moreover, an array of stressors decreases the number of VGLUT3+ neurons in the DR, where inputs from the central amygdala might play a significant role [88][82].
As for the endocrine regulation, VGLUT3 may play an important role in insulin secretion directly in the ß-cells of the Langerhans islets of the pancreas [89][83].
The parabrachial nucleus contributes to the sympathetic nervous system and cardiac activity. After stimulating cardiac sympathetic afferents, c-Fos—a neuronal marker for activity—and VGLUT3 co-localisation was found here, indicating a role of VGLUT3 in cardiovascular responses [90][84]. In line with this, ischemia-dependent changes in the expression of VGLUTs have been reported in a focal ischemia model. Ischemia is one of the leading causes of death worldwide [91][85]. Even though the central role of Glu and its receptors in the pathophysiology of cerebral ischemia and the effect of VGLUTs for excitotoxicity following an ischemia–reperfusion challenge has long been recognised [92,93[86][87][88],94], data are still sparse on this topic. In contrast to the transient increase in VGLUT1 protein levels during the first 3 days of reperfusion, VGLUT2 and 3 was reported to be downregulated in the cerebral cortex and caudoputamen of rats [95][89].

4. Characteristics of the VGLUT3 KO Mice

Among the three subtypes, VGLUT1 and 2 seem to be utmost important as their lack is fatal: VGLUT1 KO mice die around weaning, while VGLUT2 KO mice die at birth [96,97,98,99][90][91][92][93].
VGLUT1 KO animals have progressive neurological symptoms, including blindness and incoordination, supporting its role from an early stage of development [100][94]. At birth, VGLUT1 KO and WT animals are indistinguishable. However, after birth, VGLUT1 expression increases, accounting for 50% of Glu transmission in 3–5-day-old wild-type mice. In VGLUT1 KO animals during the following 2 weeks, a sharp decrease in residual activity was detected, and in mice older than 2 months, the excitatory transmission was essentially eliminated, leading to death.
VGLUT2 KO mice die due to a complete loss of stable autonomous respiratory rhythm, which is generated by the pre-Bötzinger complex [101][95]. Similar to VGLUT1 KO, the heterozygous VGLUT2 +/− mice are not obviously different from their WT littermates, despite expressing 50% less VGLUT2 protein [99][93]. However, various behavioural tests presented well that the partial loss of VGLUT2 significantly affected thalamic function. Among other things, conditioned taste aversion and defensive marble burying were impaired, while motor function, learning and memory, acute nociception, and inflammatory pain remained intact. The same study reported a nearly 50% reduction in the amplitude of spontaneous release events in VGLUT1 null hippocampal and VGLUT2 null thalamic cell cultures [99][93].
Contrary to the other two isoforms, both heterozygous and homozygous VGLUT3 KO mice are viable and reach adulthood without any need for intervention [85][79]. It is logical to assume that the elevation of VGLUT1 and 2 compensate the absence of VGLUT3 in the KO mice; however, no VGLUT1 and 2 alterations (both at the mRNA and protein level) were found in their brain [42][36]. Moreover, in adult VGLUT3 KO mice, the expression of other biochemical markers related to cholinergic, dopaminergic, GABAergic, or neuropeptidergic (substance P, encephalin) regulation were equal to the WT.
VGLUT3 KO mice show no major macroscopic anatomical discrepancies in the brain compared to their WT littermates [25][19]. Although in vitro raphe primary cell cultures that lack VGLUT3 are less likely to survive [46][40], in vivo VGLUT3 KO mice do not show reduced serotonergic cell number in their midbrain raphe nuclei. However, in the striatum and dorsal hippocampus of KO mice, the number of serotonergic varicosities was decreased, while in the ventral hippocampus, it was increased [46][40]. On a molecular level, VGLUT3 KO mice show decreased 5-HT [25,62][19][56] and ACh turnover [42][36].
Since the main VGLUT isoform expressed in the striatum, an area that has an important role in the regulation of movement, is VGLUT3, locomotor alteration in VGLUT3 KO mice could be supposed. However, their motor coordination is normal [85][79]. Interestingly, during short observations (e.g., 5–10 min open field), a reduced locomotion was detectable [84[78][79],85], while during more prolonged observations (up to 5 h), even a hyperlocomotion was observed [42][36], especially during the dark, active phase [102][96]. The reduced locomotion seems to be due to enhanced anxiety [62,84][56][78], leading to a more cautious behaviour in a new environment, while the hyperlocomotion was connected to their altered DA levels [42,102][36][96], suggesting its possible role in Parkinson disease.
In line with an altered HPA axis reactivity mentioned earlier [84[78][79],85], VGLUT3 mice were repeatedly reported to be more anxious [62,84,87,103][56][78][81][97]. This anxiety is innate and can be detected already during the early postnatal period (in 8-day-old mice) by enhanced maternal separation-induced ultrasound vocalisation (at 40–90 kHz) [62,87][56][81]. Furthermore, increased anxiety-like behaviour is still detectable in adult mice on numerous behavioural tests such as the elevated plus maze [84[78][97],103], or in marble burying, and novelty suppressed feeding paradigms [62][56].
In line with the detected hyperlocomotion, sensitivity to pharmacological treatments was also altered in the VGLUT3 KO mice [42,102,103,104,105][36][96][97][98][99]. Cocaine-induced locomotor activity was exaggerated in them [42[36][97],103], and their L-DOPA-induced dyskinesia was reduced [102,105][96][99]. Additionally, amphetamine-induced locomotion was also decreased after complete deletion of the VGLUT3 gene [106][100].
In relation to the above-mentioned drug-induced locomotor discrepancies, addictive behaviour was also altered in VGLUT3 KO mice. These animals proved to be more sensitive, since they responded to smaller amount of cocaine in a conditioned place preference test than their WT littermates [107][101] and were more responsive when it was used as a reward [104][98]. This might have a human relevance, as variations in the VGLUT3 gene in patients also correlated with severe addiction [104][98].
The previously mentioned contribution of VGLUT3 to hearing was confirmed by the loss of auditory brainstem responses in VGLUT3 KO animals [76,79,80][70][73][74]. Interestingly, the p.A211V point mutation of VGLUT3 also results in progressive deafness in humans [76][70]. However, in mice, aside from the progressive deafness, no major behavioural phenotype was observed due to the same point mutation; only an in vitro decreased VGLUT3 expression was detected [108][102].
As numerous brainstem areas involved in respiration and thermogenesis  also contain VGLUT3+ neurons (see earlier), we researchers might assume alteration in these systems as well. Indeed, despite preserved structure, the respiratory rhythm generator neurons of the brainstem in VGLUT3 KO mice fired with decreased amplitude and duration in response to hypoxic stress, which was probably due to an altered 5-HT turnover [25][19]. Moreover, their thermoregulation was also disrupted [25][19].
Learning and memory formation in VGLUT3 KO mice was also investigated, and no major disruption was found [109][103]. Indeed, an earlier study suggested the role of VGLUT1 and 2 rather than 3 in the measured parameters [110][104]. However, further studies might be needed to reveal the role of local VGLUT3 positive neurons and terminals in the processes leading to spatial, emotional, and other types of memories.
These observed changes are crucial in behavioural neuroscience, as differences between WT and KO mice in the above-mentioned parameters (e.g., locomotion, hearing) might significantly distort other results, such as anxiety-like behaviour, depressive-like behaviour, or learning paradigms.

References

  1. Burnstock, G. Do some nerve cells release more than one transmitter? Neuroscience 1976, 1, 239–248.
  2. Takamori, S.; Rhee, J.S.; Rosenmund, C.; Jahn, R. Identification of a vesicular glutamate transporter that defines a glutamatergic phenotype in neurons. Nature 2000, 407, 189–194.
  3. Robinson, M.B. Acute regulation of sodium-dependent glutamate transporters: A focus on constitutive and regulated trafficking. Neurotransm. Transp. 2006, 175, 251–275.
  4. Preobraschenski, J.; Zander, J.F.; Suzuki, T.; Ahnert-Hilger, G.; Jahn, R. Vesicular glutamate transporters use flexible anion and cation binding sites for efficient accumulation of neurotransmitter. Neuron 2014, 84, 1287–1301.
  5. Fremeau, R.T., Jr.; Burman, J.; Qureshi, T.; Tran, C.H.; Proctor, J.; Johnson, J.; Zhang, H.; Sulzer, D.; Copenhagen, D.R.; Storm-Mathisen, J.; et al. The identification of vesicular glutamate transporter 3 suggests novel modes of signaling by glutamate. Proc. Natl. Acad. Sci. USA 2002, 99, 14488–14493.
  6. Schafer, M.K.; Varoqui, H.; Defamie, N.; Weihe, E.; Erickson, J.D. Molecular cloning and functional identification of mouse vesicular glutamate transporter 3 and its expression in subsets of novel excitatory neurons. J. Biol. Chem. 2002, 277, 50734–50748.
  7. Weston, M.C.; Nehring, R.B.; Wojcik, S.M.; Rosenmund, C. Interplay between VGLUT isoforms and endophilin A1 regulates neurotransmitter release and short-term plasticity. Neuron 2011, 69, 1147–1159.
  8. Gras, C.; Herzog, E.; Bellenchi, G.C.; Bernard, V.; Ravassard, P.; Pohl, M.; Gasnier, B.; Giros, B.; El Mestikawy, S. A third vesicular glutamate transporter expressed by cholinergic and serotoninergic neurons. J. Neurosci. 2002, 22, 5442–5451.
  9. Takamori, S.; Malherbe, P.; Broger, C.; Jahn, R. Molecular cloning and functional characterization of human vesicular glutamate transporter 3. EMBO Rep. 2002, 3, 798–803.
  10. Vigneault, E.; Poirel, O.; Riad, M.; Prud’homme, J.; Dumas, S.; Turecki, G.; Fasano, C.; Mechawar, N.; El Mestikawy, S. Distribution of vesicular glutamate transporters in the human brain. Front. Neuroanat. 2015, 9, 23.
  11. Herzog, E.; Gilchrist, J.; Gras, C.; Muzerelle, A.; Ravassard, P.; Giros, B.; Gaspar, P.; El Mestikawy, S. Localization of VGLUT3, the vesicular glutamate transporter type 3, in the rat brain. Neuroscience 2004, 123, 983–1002.
  12. Harkany, T.; Hartig, W.; Berghuis, P.; Dobszay, M.B.; Zilberter, Y.; Edwards, R.H.; Mackie, K.; Ernfors, P. Complementary distribution of type 1 cannabinoid receptors and vesicular glutamate transporter 3 in basal forebrain suggests input-specific retrograde signalling by cholinergic neurons. Eur. J. Neurosci. 2003, 18, 1979–1992.
  13. Hioki, H.; Nakamura, H.; Ma, Y.F.; Konno, M.; Hayakawa, T.; Nakamura, K.C.; Fujiyama, F.; Kaneko, T. Vesicular glutamate transporter 3-expressing nonserotonergic projection neurons constitute a subregion in the rat midbrain raphe nuclei. J. Comp. Neurol. 2010, 518, 668–686.
  14. Hioki, H.; Fujiyama, F.; Nakamura, K.; Wu, S.X.; Matsuda, W.; Kaneko, T. Chemically specific circuit composed of vesicular glutamate transporter 3- and preprotachykinin B-producing interneurons in the rat neocortex. Cereb. Cortex. 2004, 14, 1266–1275.
  15. Kudo, T.; Uchigashima, M.; Miyazaki, T.; Konno, K.; Yamasaki, M.; Yanagawa, Y.; Minami, M.; Watanabe, M. Three types of neurochemical projection from the bed nucleus of the stria terminalis to the ventral tegmental area in adult mice. J. Neurosci. 2012, 32, 18035–18046.
  16. Stornetta, R.L.; Rosin, D.L.; Simmons, J.R.; McQuiston, T.J.; Vujovic, N.; Weston, M.C.; Guyenet, P.G. Coexpression of vesicular glutamate transporter-3 and gamma-aminobutyric acidergic markers in rat rostral medullary raphe and intermediolateral cell column. J. Comp. Neurol. 2005, 492, 477–494.
  17. Somogyi, J.; Baude, A.; Omori, Y.; Shimizu, H.; El Mestikawy, S.; Fukaya, M.; Shigemoto, R.; Watanabe, M.; Somogyi, P. GABAergic basket cells expressing cholecystokinin contain vesicular glutamate transporter type 3 (VGLUT3) in their synaptic terminals in hippocampus and isocortex of the rat. Eur. J. Neurosci. 2004, 19, 552–569.
  18. Harkany, T.; Holmgren, C.; Hartig, W.; Qureshi, T.; Chaudhry, F.A.; Storm-Mathisen, J.; Dobszay, M.B.; Berghuis, P.; Schulte, G.; Sousa, K.M.; et al. Endocannabinoid-independent retrograde signaling at inhibitory synapses in layer 2/3 of neocortex: Involvement of vesicular glutamate transporter 3. J. Neurosci. 2004, 24, 4978–4988.
  19. Miot, S.; Voituron, N.; Sterlin, A.; Vigneault, E.; Morel, L.; Matrot, B.; Ramanantsoa, N.; Amilhon, B.; Poirel, O.; Lepicard, E.; et al. The vesicular glutamate transporter VGLUT3 contributes to protection against neonatal hypoxic stress. J. Physiol. 2012, 590, 5183–5198.
  20. Tatti, R.; Bhaukaurally, K.; Gschwend, O.; Seal, R.P.; Edwards, R.H.; Rodriguez, I.; Carleton, A. A population of glomerular glutamatergic neurons controls sensory information transfer in the mouse olfactory bulb. Nat. Commun. 2014, 5, 3791.
  21. Rovira-Esteban, L.; Peterfi, Z.; Vikor, A.; Mate, Z.; Szabo, G.; Hajos, N. Morphological and physiological properties of CCK/CB1R-expressing interneurons in the basal amygdala. Brain Struct. Funct. 2017, 222, 3543–3565.
  22. Ormel, L.; Stensrud, M.J.; Chaudhry, F.A.; Gundersen, V. A distinct set of synaptic-like microvesicles in atroglial cells contain VGLUT3. Glia 2012, 60, 1289–1300.
  23. Li, D.; Herault, K.; Silm, K.; Evrard, A.; Wojcik, S.; Oheim, M.; Herzog, E.; Ropert, N. Lack of evidence for vesicular glutamate transporter expression in mouse astrocytes. J. Neurosci. 2013, 33, 4434–4455.
  24. Nakamura, K.; Matsumura, K.; Kobayashi, S.; Kaneko, T. Sympathetic premotor neurons mediating thermoregulatory functions. Neurosci. Res. 2005, 51, 1–8.
  25. Oliveira, A.L.; Hydling, F.; Olsson, E.; Shi, T.; Edwards, R.H.; Fujiyama, F.; Kaneko, T.; Hokfelt, T.; Cullheim, S.; Meister, B. Cellular localization of three vesicular glutamate transporter mRNAs and proteins in rat spinal cord and dorsal root ganglia. Synapse 2003, 50, 117–129.
  26. Rosin, D.L.; Chang, D.A.; Guyenet, P.G. Afferent and efferent connections of the rat retrotrapezoid nucleus. J. Comp. Neurol. 2006, 499, 64–89.
  27. Zerari-Mailly, F.; Braud, A.; Davido, N.; Toure, B.; Azerad, J.; Boucher, Y. Glutamate control of pulpal blood flow in the incisor dental pulp of the rat. Eur. J. Oral Sci. 2012, 120, 402–407.
  28. Munguba, G.C.; Camp, A.S.; Risco, M.; Tapia, M.L.; Bhattacharya, S.K.; Lee, R.K. Vesicular glutamate transporter 3 in age-dependent optic neuropathy. Mol. Vis. 2011, 17, 413–419.
  29. Stensrud, M.J.; Chaudhry, F.A.; Leergaard, T.B.; Bjaalie, J.G.; Gundersen, V. Vesicular glutamate transporter-3 in the rodent brain: Vesicular colocalization with vesicular gamma-aminobutyric acid transporter. J. Comp. Neurol. 2013, 521, 3042–3056.
  30. Del Pino, I.; Brotons-Mas, J.R.; Marques-Smith, A.; Marighetto, A.; Frick, A.; Marin, O.; Rico, B. Abnormal wiring of CCK(+) basket cells disrupts spatial information coding. Nat. Neurosci. 2017, 20, 784–792.
  31. Stensrud, M.J.; Sogn, C.J.; Gundersen, V. Immunogold characteristics of VGLUT3-positive GABAergic nerve terminals suggest corelease of glutamate. J. Comp. Neurol. 2015, 523, 2698–2713.
  32. Jalabert, M.; Aston-Jones, G.; Herzog, E.; Manzoni, O.; Georges, F. Role of the bed nucleus of the stria terminalis in the control of ventral tegmental area dopamine neurons. Prog. Neuropsychopharmacol. Biol. Psychiatry 2009, 33, 1336–1346.
  33. Omiya, Y.; Uchigashima, M.; Konno, K.; Yamasaki, M.; Miyazaki, T.; Yoshida, T.; Kusumi, I.; Watanabe, M. VGluT3-expressing CCK-positive basket cells construct invaginating synapses enriched with endocannabinoid signaling proteins in particular cortical and cortex-like amygdaloid regions of mouse brains. J. Neurosci. 2015, 35, 4215–4228.
  34. Case, D.T.; Burton, S.D.; Gedeon, J.Y.; Williams, S.G.; Urban, N.N.; Seal, R.P. Layer- and cell type-selective co-transmission by a basal forebrain cholinergic projection to the olfactory bulb. Nat. Commun. 2017, 8, 652.
  35. Nickerson Poulin, A.; Guerci, A.; El Mestikawy, S.; Semba, K. Vesicular glutamate transporter 3 immunoreactivity is present in cholinergic basal forebrain neurons projecting to the basolateral amygdala in rat. J. Comp. Neurol. 2006, 498, 690–711.
  36. Gras, C.; Amilhon, B.; Lepicard, E.M.; Poirel, O.; Vinatier, J.; Herbin, M.; Dumas, S.; Tzavara, E.T.; Wade, M.R.; Nomikos, G.G.; et al. The vesicular glutamate transporter VGLUT3 synergizes striatal acetylcholine tone. Nat. Neurosci. 2008, 11, 292–300.
  37. Higley, M.J.; Gittis, A.H.; Oldenburg, I.A.; Balthasar, N.; Seal, R.P.; Edwards, R.H.; Lowell, B.B.; Kreitzer, A.C.; Sabatini, B.L. Cholinergic interneurons mediate fast VGluT3-dependent glutamatergic transmission in the striatum. PLoS ONE 2011, 6, e19155.
  38. Nelson, A.B.; Bussert, T.G.; Kreitzer, A.C.; Seal, R.P. Striatal cholinergic neurotransmission requires VGLUT3. J. Neurosci. 2014, 34, 8772–8777.
  39. Shutoh, F.; Ina, A.; Yoshida, S.; Konno, J.; Hisano, S. Two distinct subtypes of serotonergic fibers classified by co-expression with vesicular glutamate transporter 3 in rat forebrain. Neurosci. Lett. 2008, 432, 132–136.
  40. Voisin, A.N.; Mnie-Filali, O.; Giguere, N.; Fortin, G.M.; Vigneault, E.; El Mestikawy, S.; Descarries, L.; Trudeau, L.E. Axonal segregation and role of the vesicular glutamate transporter VGLUT3 in serotonin neurons. Front. Neuroanat. 2016, 10, 39.
  41. Calizo, L.H.; Akanwa, A.; Ma, X.; Pan, Y.Z.; Lemos, J.C.; Craige, C.; Heemstra, L.A.; Beck, S.G. Raphe serotonin neurons are not homogenous: Electrophysiological, morphological and neurochemical evidence. Neuropharmacology 2011, 61, 524–543.
  42. Ren, J.; Friedmann, D.; Xiong, J.; Liu, C.D.; Ferguson, B.R.; Weerakkody, T.; DeLoach, K.E.; Ran, C.; Pun, A.; Sun, Y.; et al. Anatomically defined and functionally distinct dorsal raphe serotonin sub-systems. Cell 2018, 175, 472–487 e420.
  43. Gagnon, D.; Parent, M. Distribution of VGLUT3 in highly collateralized axons from the rat dorsal raphe nucleus as revealed by single-neuron reconstructions. PLoS ONE 2014, 9, e87709.
  44. Commons, K.G. Locally collateralizing glutamate neurons in the dorsal raphe nucleus responsive to substance P contain vesicular glutamate transporter 3 (VGLUT3). J. Chem. Neuroanat. 2009, 38, 273–281.
  45. Fu, W.; Le Maitre, E.; Fabre, V.; Bernard, J.F.; David Xu, Z.Q.; Hokfelt, T. Chemical neuroanatomy of the dorsal raphe nucleus and adjacent structures of the mouse brain. J. Comp. Neurol. 2010, 518, 3464–3494.
  46. Liu, Z.; Zhou, J.; Li, Y.; Hu, F.; Lu, Y.; Ma, M.; Feng, Q.; Zhang, J.E.; Wang, D.; Zeng, J.; et al. Dorsal raphe neurons signal reward through 5-HT and glutamate. Neuron 2014, 81, 1360–1374.
  47. Zou, W.J.; Song, Y.L.; Wu, M.Y.; Chen, X.T.; You, Q.L.; Yang, Q.; Luo, Z.Y.; Huang, L.; Kong, Y.; Feng, J.; et al. A discrete serotonergic circuit regulates vulnerability to social stress. Nat. Commun. 2020, 11, 4218.
  48. Wang, H.L.; Zhang, S.; Qi, J.; Wang, H.; Cachope, R.; Mejias-Aponte, C.A.; Gomez, J.A.; Mateo-Semidey, G.E.; Beaudoin, G.M.J.; Paladini, C.A.; et al. Dorsal raphe dual serotonin-glutamate neurons drive reward by establishing excitatory synapses on VTA mesoaccumbens dopamine neurons. Cell Rep. 2019, 26, 1128–1142.e7.
  49. Sengupta, A.; Holmes, A. A Discrete dorsal raphe to basal amygdala 5-HT circuit calibrates aversive memory. Neuron 2019, 103, 489–505.e7.
  50. Sengupta, A.; Bocchio, M.; Bannerman, D.M.; Sharp, T.; Capogna, M. Control of Amygdala Circuits by 5-HT Neurons via 5-HT and Glutamate Cotransmission. J. Neurosci. 2017, 37, 1785–1796.
  51. Martin-Ibanez, R.; Jenstad, M.; Berghuis, P.; Edwards, R.H.; Hioki, H.; Kaneko, T.; Mulder, J.; Canals, J.M.; Ernfors, P.; Chaudhry, F.A.; et al. Vesicular glutamate transporter 3 (VGLUT3) identifies spatially segregated excitatory terminals in the rat substantia nigra. Eur. J. Neurosci. 2006, 23, 1063–1070.
  52. Sos, K.E.; Mayer, M.I.; Cserep, C.; Takacs, F.S.; Szonyi, A.; Freund, T.F.; Nyiri, G. Cellular architecture and transmitter phenotypes of neurons of the mouse median raphe region. Brain Struct. Funct. 2017, 222, 287–299.
  53. Belmer, A.; Beecher, K.; Jacques, A.; Patkar, O.L.; Sicherre, F.; Bartlett, S.E. Axonal Non-segregation of the vesicular glutamate transporter VGLUT3 within serotonergic projections in the mouse forebrain. Front. Cell Neurosci. 2019, 13, 193.
  54. Gaspar, P.; Lillesaar, C. Probing the diversity of serotonin neurons. Philos. Trans. R Soc. Lond B Biol. Sci. 2012, 367, 2382–2394.
  55. Senft, R.A.; Freret, M.E.; Sturrock, N.; Dymecki, S.M. Neurochemically and hodologically distinct ascending VGLUT3 versus serotonin subsystems comprise the r2-Pet1 median raphe. J. Neurosci. 2021, 41, 2581–2600.
  56. Amilhon, B.; Lepicard, E.; Renoir, T.; Mongeau, R.; Popa, D.; Poirel, O.; Miot, S.; Gras, C.; Gardier, A.M.; Gallego, J.; et al. VGLUT3 (vesicular glutamate transporter type 3) contribution to the regulation of serotonergic transmission and anxiety. J. Neurosci. 2010, 30, 2198–2210.
  57. El Mestikawy, S.; Wallen-Mackenzie, A.; Fortin, G.M.; Descarries, L.; Trudeau, L.E. From glutamate co-release to vesicular synergy: Vesicular glutamate transporters. Nat. Rev. Neurosci. 2011, 12, 204–216.
  58. Fasano, C.; Rocchetti, J.; Pietrajtis, K.; Zander, J.F.; Manseau, F.; Sakae, D.Y.; Marcus-Sells, M.; Ramet, L.; Morel, L.J.; Carrel, D.; et al. Regulation of the hippocampal network by VGLUT3-positive CCK- GABAergic basket cells. Front. Cell Neurosci. 2017, 11, 140.
  59. Pelkey, K.A.; Calvigioni, D.; Fang, C.; Vargish, G.; Ekins, T.; Auville, K.; Wester, J.C.; Lai, M.; Mackenzie-Gray Scott, C.; Yuan, X.; et al. Paradoxical network excitation by glutamate release from VGluT3(+) GABAergic interneurons. Elife 2020, 9, e51996.
  60. Zimmermann, J.; Herman, M.A.; Rosenmund, C. Co-release of glutamate and GABA from single vesicles in GABAergic neurons exogenously expressing VGLUT3. Front. Synaptic Neurosci. 2015, 7, 16.
  61. Cropper, E.C.; Jing, J.; Vilim, F.S.; Weiss, K.R. Peptide cotransmitters as dynamic, intrinsic modulators of network activity. Front. Neural Circ. 2018, 12, 78.
  62. Nusbaum, M.P.; Blitz, D.M.; Marder, E. Functional consequences of neuropeptide and small-molecule co-transmission. Nat. Rev. Neurosci. 2017, 18, 389–403.
  63. Larsson, M.; Broman, J. Synaptic Organization of VGLUT3 Expressing low-threshold mechanosensitive c fiber terminals in the rodent spinal cord. eNeuro 2019, 6, ENEURO.0007-19.2019.
  64. Crepel, F.; Galante, M.; Habbas, S.; McLean, H.; Daniel, H. Role of the vesicular transporter VGLUT3 in retrograde release of glutamate by cerebellar Purkinje cells. J. Neurophysiol. 2011, 105, 1023–1032.
  65. Fuzik, J.; Zeisel, A.; Mate, Z.; Calvigioni, D.; Yanagawa, Y.; Szabo, G.; Linnarsson, S.; Harkany, T. Integration of electrophysiological recordings with single-cell RNA-seq data identifies neuronal subtypes. Nat. Biotechnol. 2016, 34, 175–183.
  66. Kohus, Z.; Kali, S.; Rovira-Esteban, L.; Schlingloff, D.; Papp, O.; Freund, T.F.; Hajos, N.; Gulyas, A.I. Properties and dynamics of inhibitory synaptic communication within the CA3 microcircuits of pyramidal cells and interneurons expressing parvalbumin or cholecystokinin. J. Physiol. 2016, 594, 3745–3774.
  67. Grimes, W.N.; Seal, R.P.; Oesch, N.; Edwards, R.H.; Diamond, J.S. Genetic targeting and physiological features of VGLUT3+ amacrine cells. Vis. Neurosci. 2011, 28, 381–392.
  68. Peng, Z.; Wang, G.P.; Zeng, R.; Guo, J.Y.; Chen, C.F.; Gong, S.S. Temporospatial expression and cellular localization of VGLUT3 in the rat cochlea. Brain Res. 2013, 1537, 100–110.
  69. Obholzer, N.; Wolfson, S.; Trapani, J.G.; Mo, W.; Nechiporuk, A.; Busch-Nentwich, E.; Seiler, C.; Sidi, S.; Sollner, C.; Duncan, R.N.; et al. Vesicular glutamate transporter 3 is required for synaptic transmission in zebrafish hair cells. J. Neurosci. 2008, 28, 2110–2118.
  70. Ruel, J.; Emery, S.; Nouvian, R.; Bersot, T.; Amilhon, B.; Van Rybroek, J.M.; Rebillard, G.; Lenoir, M.; Eybalin, M.; Delprat, B.; et al. Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice. Am. J. Hum. Genet. 2008, 83, 278–292.
  71. Noh, J.; Seal, R.P.; Garver, J.A.; Edwards, R.H.; Kandler, K. Glutamate co-release at GABA/glycinergic synapses is crucial for the refinement of an inhibitory map. Nat. Neurosci. 2010, 13, 232–238.
  72. Joshi, Y.; Petit, C.P.; Miot, S.; Guillet, M.; Sendin, G.; Bourien, J.; Wang, J.; Pujol, R.; El Mestikawy, S.; Puel, J.L.; et al. VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons. J. Physiol. 2021, 599, 5397–5416.
  73. Seal, R.P.; Akil, O.; Yi, E.; Weber, C.M.; Grant, L.; Yoo, J.; Clause, A.; Kandler, K.; Noebels, J.L.; Glowatzki, E.; et al. Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3. Neuron 2008, 57, 263–275.
  74. Akil, O.; Seal, R.P.; Burke, K.; Wang, C.; Alemi, A.; During, M.; Edwards, R.H.; Lustig, L.R. Restoration of hearing in the VGLUT3 knockout mouse using virally mediated gene therapy. Neuron 2012, 75, 283–293.
  75. Kim, K.X.; Payne, S.; Yang-Hood, A.; Li, S.Z.; Davis, B.; Carlquist, J.; Babak, V.-G.; Gantz, J.A.; Kallogjeri, D.; Fitzpatrick, J.A.J.; et al. Vesicular glutamatergic transmission in noise-induced loss and repair of cochlear ribbon synapses. J. Neurosci. 2019, 39, 4434–4447.
  76. Honsek, S.D.; Seal, R.P.; Sandkuhler, J. Presynaptic inhibition of optogenetically identified VGluT3+ sensory fibres by opioids and baclofen. Pain 2015, 156, 243–251.
  77. Lou, S.; Duan, B.; Vong, L.; Lowell, B.B.; Ma, Q. Runx1 controls terminal morphology and mechanosensitivity of VGLUT3-expressing C-mechanoreceptors. J. Neurosci. 2013, 33, 870–882.
  78. Balazsfi, D.; Fodor, A.; Torok, B.; Ferenczi, S.; Kovacs, K.J.; Haller, J.; Zelena, D. Enhanced innate fear and altered stress axis regulation in VGluT3 knockout mice. Stress 2018, 21, 151–161.
  79. Horvath, H.R.; Fazekas, C.L.; Balazsfi, D.; Jain, S.K.; Haller, J.; Zelena, D. Contribution of vesicular glutamate transporters to stress response and related psychopathologies: Studies in VGluT3 knockout mice. Cell Mol. Neurobiol. 2018, 38, 37–52.
  80. Olivan, A.M.; Perez-Rodriguez, R.; Roncero, C.; Arce, C.; Gonzalez, M.P.; Oset-Gasque, M.J. Plasma membrane and vesicular glutamate transporter expression in chromaffin cells of bovine adrenal medulla. J. Neurosci. Res. 2011, 89, 44–57.
  81. Balazsfi, D.; Farkas, L.; Csikota, P.; Fodor, A.; Zsebok, S.; Haller, J.; Zelena, D. Sex-dependent role of vesicular glutamate transporter 3 in stress-regulation and related anxiety phenotype during the early postnatal period. Stress 2016, 19, 434–438.
  82. Prakash, N.; Stark, C.J.; Keisler, M.N.; Luo, L.; Der-Avakian, A.; Dulcis, D. Serotonergic plasticity in the dorsal raphe nucleus characterizes susceptibility and resilience to anhedonia. J. Neurosci. 2020, 40, 569–584.
  83. Gammelsaeter, R.; Coppola, T.; Marcaggi, P.; Storm-Mathisen, J.; Chaudhry, F.A.; Attwell, D.; Regazzi, R.; Gundersen, V. A role for glutamate transporters in the regulation of insulin secretion. PLoS ONE 2011, 6, e22960.
  84. Guo, Z.L.; Moazzami, A.R.; Longhurst, J.C. Stimulation of cardiac sympathetic afferents activates glutamatergic neurons in the parabrachial nucleus: Relation to neurons containing nNOS. Brain Res. 2005, 1053, 97–107.
  85. Benjamin, E.J.; Muntner, P.; Alonso, A.; Bittencourt, M.S.; Callaway, C.W.; Carson, A.P.; Chamberlain, A.M.; Chang, A.R.; Cheng, S.; Das, S.R.; et al. Heart disease and stroke statistics-2019 update: A report from the american heart association. Circulation 2019, 139, e56–e528.
  86. Krzyzanowska, W.; Pomierny, B.; Budziszewska, B.; Filip, M.; Pera, J. N-Acetylcysteine and ceftriaxone as preconditioning strategies in focal brain ischemia: Influence on glutamate transporters expression. Neurotox. Res. 2016, 29, 539–550.
  87. Castillo, J.; Alvarez-Sabin, J.; Davalos, A.; Diez-Tejedor, E.; Lizasoain, I.; Martinez-Vila, E.; Vivancos, J.; Zarranz, J.J. Consensus review. Pharmacological neuroprotection in cerebral ischemia: Is it still a therapeutic option? Neurologia 2003, 18, 368–384.
  88. Krzyzanowska, W.; Pomierny, B.; Bystrowska, B.; Pomierny-Chamiolo, L.; Filip, M.; Budziszewska, B.; Pera, J. Ceftriaxone- and N-acetylcysteine-induced brain tolerance to ischemia: Influence on glutamate levels in focal cerebral ischemia. PLoS ONE 2017, 12, e0186243.
  89. Sanchez-Mendoza, E.; Burguete, M.C.; Castello-Ruiz, M.; Gonzalez, M.P.; Roncero, C.; Salom, J.B.; Arce, C.; Canadas, S.; Torregrosa, G.; Alborch, E.; et al. Transient focal cerebral ischemia significantly alters not only EAATs but also VGLUTs expression in rats: Relevance of changes in reactive astroglia. J. Neurochem. 2010, 113, 1343–1355.
  90. Callaerts-Vegh, Z.; Moechars, D.; Van Acker, N.; Daneels, G.; Goris, I.; Leo, S.; Naert, A.; Meert, T.; Balschun, D.; D’Hooge, R. Haploinsufficiency of VGluT1 but not VGluT2 impairs extinction of spatial preference and response suppression. Behav. Brain Res. 2013, 245, 13–21.
  91. Wallen-Mackenzie, A.; Gezelius, H.; Thoby-Brisson, M.; Nygard, A.; Enjin, A.; Fujiyama, F.; Fortin, G.; Kullander, K. Vesicular glutamate transporter 2 is required for central respiratory rhythm generation but not for locomotor central pattern generation. J. Neurosci. 2006, 26, 12294–12307.
  92. Wallen-Mackenzie, A.; Wootz, H.; Englund, H. Genetic inactivation of the vesicular glutamate transporter 2 (VGLUT2) in the mouse: What have we learnt about functional glutamatergic neurotransmission? Ups J. Med. Sci. 2010, 115, 11–20.
  93. Moechars, D.; Weston, M.C.; Leo, S.; Callaerts-Vegh, Z.; Goris, I.; Daneels, G.; Buist, A.; Cik, M.; van der Spek, P.; Kass, S.; et al. Vesicular glutamate transporter VGLUT2 expression levels control quantal size and neuropathic pain. J. Neurosci. 2006, 26, 12055–12066.
  94. Fremeau, R.T., Jr.; Kam, K.; Qureshi, T.; Johnson, J.; Copenhagen, D.R.; Storm-Mathisen, J.; Chaudhry, F.A.; Nicoll, R.A.; Edwards, R.H. Vesicular glutamate transporters 1 and 2 target to functionally distinct synaptic release sites. Science 2004, 304, 1815–1819.
  95. Gezelius, H.; Wallen-Mackenzie, A.; Enjin, A.; Lagerstrom, M.; Kullander, K. Role of glutamate in locomotor rhythm generating neuronal circuitry. J. Physiol.-Paris 2006, 100, 297–303.
  96. Divito, C.B.; Steece-Collier, K.; Case, D.T.; Williams, S.P.; Stancati, J.A.; Zhi, L.; Rubio, M.E.; Sortwell, C.E.; Collier, T.J.; Sulzer, D.; et al. Loss of VGLUT3 Produces circadian-dependent hyperdopaminergia and ameliorates motor dysfunction and l-dopa-mediated dyskinesias in a model of parkinson’s disease. J. Neurosci. 2015, 35, 14983–14999.
  97. Sakae, D.Y.; Ramet, L.; Henrion, A.; Poirel, O.; Jamain, S.; El Mestikawy, S.; Daumas, S. Differential expression of VGLUT3 in laboratory mouse strains: Impact on drug-induced hyperlocomotion and anxiety-related behaviors. Genes Brain Behav. 2019, 18, e12528.
  98. Sakae, D.Y.; Marti, F.; Lecca, S.; Vorspan, F.; Martin-Garcia, E.; Morel, L.J.; Henrion, A.; Gutierrez-Cuesta, J.; Besnard, A.; Heck, N.; et al. The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens. Mol. Psychiatry 2015, 20, 1448–1459.
  99. Gangarossa, G.; Guzman, M.; Prado, V.F.; Prado, M.A.; Daumas, S.; El Mestikawy, S.; Valjent, E. Role of the atypical vesicular glutamate transporter VGLUT3 in l-DOPA-induced dyskinesia. Neurobiol. Dis. 2016, 87, 69–79.
  100. Mansouri-Guilani, N.; Bernard, V.; Vigneault, E.; Vialou, V.; Daumas, S.; El Mestikawy, S.; Gangarossa, G. VGLUT3 gates psychomotor effects induced by amphetamine. J. Neurochem. 2019, 148, 779–795.
  101. Fontaine, H.M.; Silva, P.R.; Neiswanger, C.; Tran, R.; Abraham, A.D.; Land, B.B.; Neumaier, J.F.; Chavkin, C. Stress decreases serotonin tone in the nucleus accumbens in male mice to promote aversion and potentiate cocaine preference via decreased stimulation of 5-HT1B receptors. Neuropsychopharmacology 2021.
  102. Ramet, L.; Zimmermann, J.; Bersot, T.; Poirel, O.; De Gois, S.; Silm, K.; Sakae, D.Y.; Mansouri-Guilani, N.; Bourque, M.J.; Trudeau, L.E.; et al. Characterization of a human point mutation of VGLUT3 (p.A211V) in the rodent brain suggests a nonuniform distribution of the transporter in synaptic vesicles. J. Neurosci. 2017, 37, 4181–4199.
  103. Fazekas, C.L.; Balazsfi, D.; Horvath, H.R.; Balogh, Z.; Aliczki, M.; Puhova, A.; Balagova, L.; Chmelova, M.; Jezova, D.; Haller, J.; et al. Consequences of VGluT3 deficiency on learning and memory in mice. Physiol. Behav. 2019, 212, 112688.
  104. Cheng, X.R.; Yang, Y.; Zhou, W.X.; Zhang, Y.X. Expression of VGLUTs contributes to degeneration and acquisition of learning and memory. Neurobiol. Learn. Mem. 2011, 95, 361–375.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
ScholarVision Creations
Feedback