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

Abstract

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.

Keywords: Behavior; Catecholaminergic system; Hormones; Hypothalamic-pituitary-adrenocortical axis; VGluT3 knockout mice.

Fig. 1

Glutamatergic regulation of the catecholaminergic stress-effector system. One of the main output systems of the stressor-activated brain areas is the autonomic preganglionic neurons (red) originating from different parts of the hypothalamus and brainstem. They project to the para- and prevertebral sympathetic ganglia (sympatho-neural system; blue), or to chromaffin cells in the adrenal medulla (sympatho-adrenomedullary system, SAS; green). From postganglionic nerve endings mainly noradrenaline is released, while adrenal medulla synthetize presumably adrenaline, as hormone. Glutamate receptors were found at all level of the axis (brain, spinal cord, adrenal medulla) with variable expression. VGluT2 transporter was detected in brainstem catecholaminergic groups (C1, C2, C3, A2 but not A5, A6/locus coeruleus) (Stornetta et al. 2002a, b) and excitatory spinal cord interneurons (Seal et al. 2016). A5/C1 catecholaminergic cell groups of the brainstem, AMPA R,S-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, EAAT excitatory amino acid transporter, Glu glutamate, mGluR metabotrop glutamate receptors, NMDA N-methyl-d-aspartate, PVN paraventricular nucleus of the hypothalamus, VGluT vesicular glutamate transporter (Color figure online)

Fig. 2

Glutamatergic regulation of the hypothalamic-pituitary-adrenocortical axis (HPA). According to Selye the HPA axis is the main effector of stress adaptation. The neuropeptides CRH and AVP are released from the PVN and reach the anterior lobe of the pituitary though the portal vessels. As a consequence, ACTH is released to the general circulation and in the adrenal cortex glucocorticoids are synthetized. Beside their effector function glucocorticoids provide negative feedback. Although glutamate receptors were detected at all three levels of the axis, but not on corticotroph cells of the pituitary or an adrenocortical cells (rather in medulla). Thus, its contribution to HPA axis regulation seems to be mostly central. Among the transporters VGluT 1 and 2 were found in the hypothalamus (Herman et al. 2004). At pituitary level CRHergic axon terminals contained VGluT2 (Wittmann et al. 2013), and the corticotroph cells had VGluT1 (Kocsis et al. 2010). The chromaffin cells of the adrenal medulla contained VGluT3 (Olivan et al. 2011), but its contribution to glucocorticoid secretion in the adrenal cortex is questionable. ACTH adrenocorticotropin, AMPA R,S-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, AVP arginine vasopressin, CRH corticotropin-releasing hormone, Glu: glutamate, HPA hypothalamic-pituitary-adrenocortical axis, mGluR metabotrop glutamate receptors, NMDA N-methy-d-aspartate, PVN paraventricular nucleus of the hypothalamus

Fig. 3

Open field activity of the vesicular glutamate transporter 3 (VGluT3) knockout mice. Locomotor activity was observed during a 5 min test by Ethovision in a Plexiglas chamber (40 × 36 × 19 cm). Representative example. WT wildtype, KO vesicular glutamate transporter 3 knockout