Glutamatergic and dopaminergic neurons in the mouse ventral tegmental area

Abstract

The ventral tegmental area (VTA) comprises dopamine (DA), GABA and glutamate (Glu) neurons. Some rat VTA Glu neurons, expressing vesicular glutamate transporter 2 (VGluT2), co-express tyrosine hydroxylase (TH). While transgenic mice are now being used in attempts to determine the role of VGluT2/TH neurons in reward and neuronal signaling, such neurons have not been characterized in mouse tissue. By cellular detection of VGluT2-mRNA and TH-immunoreactivity (TH-IR), we determined the cellular expression of VGluT2-mRNA within VTA TH-IR neurons in the mouse. We found that some mouse VGluT2 neurons co-expressed TH-IR, but their frequency was lower than in the rat. To determine whether low expression of TH mRNA or TH-IR accounts for this low frequency, we evaluated VTA cellular co-expression of TH-transcripts and TH-protein. Within the medial aspects of the VTA, some neurons expressed TH mRNA but lacked TH-IR; among them a subset co-expressed VGluT2 mRNA. To determine if lack of VTA TH-IR was due to TH trafficking, we tagged VTA TH neurons by cre-inducible expression of mCherry in TH::Cre mice. By dual immunofluorescence, we detected axons containing mCherry, but lacking TH-IR, in the lateral habenula, indicating that mouse low frequency of VGluT2 mRNA (+)/TH-IR (+) neurons is due to lack of synthesis of TH protein, rather than TH-protein trafficking. In conclusion, VGluT2 neurons are present in the rat and mouse VTA, but they differ in the populations of VGluT2/TH and TH neurons. We reveal that under normal conditions, the translation of TH protein is suppressed in the mouse mesohabenular TH neurons.

Role for VGLUT2 in selective vulnerability of midbrain dopamine neurons

“…More than 90% of both SNc and VTA DA neurons labeled with zsGreen ( Figure 5D). However, in the adult mouse and other mammals, only a subset of midbrain DA neurons express VGLUT2 (or VGLUT2 Cre ), and these are more abundant in the medial VTA (5,7,8,35,36). Together, these results indicate that most SNc and VTA DA neurons transiently express VGLUT2 during development, but only a small subset continue to express VGLUT2 in the adult.…”

“…But what might this teach us of the underlying neurobiology, or about selective DA neuron vulnerability? In the mouse, rat, marmoset, and human, endogenous VGLUT2 expression has been colocalized to a subset of midbrain DA neurons (5,7,8,45). The fraction varies by subregion and projection target, and estimates range across species, study, and approach, but generally only a minority (<20%) of midbrain DA neurons express detectable levels of VGLUT2 in the adult.…”

“…A subset of midbrain DA neurons corelease glutamate and express vesicular glutamate transporter 2 (VGLUT2) in the adult mouse, rat, primate, and human (5)(6)(7)(8)(9). Evidence indicates that VGLUT2 is expressed more broadly in midbrain DA neurons during development (10)(11)(12); but VGLUT2 expression is restricted to smaller subsets in the adult mouse, when colocalization with DA markers is most pronounced in medial regions of the VTA (7,10,13).…”

“…Evidence indicates that VGLUT2 is expressed more broadly in midbrain DA neurons during development (10)(11)(12); but VGLUT2 expression is restricted to smaller subsets in the adult mouse, when colocalization with DA markers is most pronounced in medial regions of the VTA (7,10,13). It is these medial VTA DA neurons that are generally spared in human PD and in PD animal models (14)(15)(16)(17)(18)(19), portending a potentially important relationship between VGLUT2 expression and vulnerability to DA neuron degeneration.…”

Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit

“…[48][49][50] Moreover, the VTA contains few glutamatergic neurons which are located more medially in the VTA. 51,52 On the basis of the location of the recorded neurons in the VTA (mostly lateral and not medial), their spontaneous firing and membrane properties (for example, large I h , afterhyperpolarization and excitability profile, see Supplementary Figures 5 and 6), it is likely that DA neurons, and not glutamatergic neurons, in the VTA that project to the NAc, and not to the cortex, were examined in the present study. The membrane properties of VTA-DA neurons were similar in mice treated with saline, ketamine or (2R,6R)-HNK ( Supplementary Figures 5 and 6).…”