Contribution of Vesicular Glutamate Transporters to StressResponse and Related Psychopathologies: Studies in VGluT3Knockout Mice

Abstract Maintenance of the homeostasis in a constantlychanging environment is a fundamental process of life.Disturbances of the homeostatic balance is defined as stressresponse and is induced by wide variety of challengescalled stressors. Being the main excitatory neurotransmitterof the central nervous system glutamate is important in theadaptation process of stress regulating both the catecholaminergicsystem and the hypothalamic-pituitaryadrenocorticalaxis. Data are accumulating about the roleof different glutamatergic receptors at all levels of theseaxes, but little is known about the contribution of differentvesicular glutamate transporters (VGluT1-3) characterizingthe glutamatergic neurons. Here we summarize basicknowledge about VGluTs, their role in physiological regulationof stress adaptation, as well as their contribution tostress-related psychopathology. Most of our knowledgecomes from the VGluT3 knockout mice, as VGluT1 and 2knockouts are not viable. VGluT3 was discovered laterthan, and is not as widespread as the VGluT1 and 2. It mayco-localize with other transmitters, and participate in retrogradesignaling; as such its role might be unique. Previousreports using VGluT3 knockout mice showedenhanced anxiety and innate fear compared to wild type.Moreover, these knockout animals had enhanced restingcorticotropin-releasing hormone mRNA levels in thehypothalamus and disturbed glucocorticoid stress responses.In conclusion, VGluT3 participates in stress adaptationregulation. The neuroendocrine changes observed inVGluT3 knockout mice may contribute to their anxious,fearful phenotype.Keywords Catecholaminergic system Hypothalamicpituitary-adrenocortical axis VGluT3 knockout mice Hormones Behavio