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

Maintenance of the homeostasis in a constantly changing environment is a fundamental process of life. Disturbances of the homeostatic balance is defined as stress response and is induced by wide variety of challenges called stressors. Being the main excitatory neurotransmitter of the central nervous system glutamate is important in the adaptation process of stress regulating both the catecholaminergic system and the hypothalamic-pituitary-adrenocortical axis. Data are accumulating about the role of different glutamatergic receptors at all levels of these axes, but little is known about the contribution of different vesicular glutamate transporters (VGluT1-3) characterizing the glutamatergic neurons. Here we summarize basic knowledge about VGluTs, their role in physiological regulation of stress adaptation, as well as their contribution to stress-related psychopathology. Most of our knowledge comes from the VGluT3 knockout mice, as VGluT1 and 2 knockouts are not viable. VGluT3 was discovered later than, and is not as widespread as the VGluT1 and 2. It may co-localize with other transmitters, and participate in retrograde signaling; as such its role might be unique. Previous reports using VGluT3 knockout mice showed enhanced anxiety and innate fear compared to wild type. Moreover, these knockout animals had enhanced resting corticotropin-releasing hormone mRNA levels in the hypothalamus and disturbed glucocorticoid stress responses. In conclusion, VGluT3 participates in stress adaptation regulation. The neuroendocrine changes observed in VGluT3 knockout mice may contribute to their anxious, fearful phenotype.