Characterization of NPY Y2 receptor protein expression in the mouse brain. II. Coexistence with NPY, the Y1 receptor, and other neurotransmitter‐related molecules

Abstract

Neuropeptide Y (NPY) is widely expressed in the brain and its biological effects are mediated through a variety of receptors. We examined, using immunohistochemistry, expression of the Y2 receptor (R) protein in the adult mouse brain and its association with NPY and the Y1R, as well as a range of additional neurotransmitters and signaling-related molecules, which previously have not been defined. Our main focus was on the hippocampal formation (HiFo), amygdaloid complex, and hypothalamus, considering the known functions of NPY and the wide expression of NPY, Y1R, and Y2R in these regions. Y2R-like immunoreactivity (-LI) was distributed in nerve fibers/terminal endings throughout the brain axis, without apparent colocalization with NPY or the Y1R. Occasional coexistence between NPY- and Y1R-LI was found in the HiFo. Following colchicine treatment, Y2R-LI accumulated in cell bodies that coexpressed γ-aminobutyric acid (GABA) in a population of cells in the amygdaloid complex and lateral septal nucleus, but not in the HiFo. Instead, Y2R-positive nerve terminals appeared to surround GABA-immunoreactive (ir) cells in the HiFo and other neuronal populations, e.g., NPY-ir cells in HiFo and tyrosine hydroxylase-ir cells in the hypothalamus. In the HiFo, Y2R-ir mossy fibers coexpressed GABA, glutamic acid decarboxylase 67 and calbindin, and Y2R-LI was found in the same fibers that contained the presynaptic metabotropic glutamate receptor 2, but not together with any of the three vesicular glutamate transporters. Our findings provide further support that Y2R is mostly presynaptic, and that Y2Rs thus have a modulatory role in mediating presynaptic neurotransmitter release.

Regulatory functions of limbic Y1 receptors in body weight and anxiety uncovered by conditional knockout and maternal care

“…The hippocampus is an important component of neuronal circuitry controlling anxiety-related behaviors and stress responses and seems to inhibit the HPA axis through glutamate-GABA connections (31). Previous studies have shown that Y1Rs are associated with glutamate-positive and NPYpositive neurons in hippocampal subregions, providing the anatomical basis for the Y1R-mediated modulation of glutamate and NPY release (32,33). Thus, we postulate that the selective inactivation of Y1Rs in principal excitatory neurons of hippocampus might stimulate HPA axis via the glutamatergic output.…”

Central nervous system neuropeptide Y signaling via the Y1 receptor partially dissociates feeding behavior from lipoprotein metabolism in lean rats

“…Because we show that Y1 receptor activation has a greater effect than activation of the Y2 receptor on lipoprotein metabolism, it informs of potential structure-function relationships of the NPY-regulated neural circuitry involved. There is a reportedly close physical localization and apparent functional relationship between NPY Y1 and Y2 receptors in neurons found within the ARC, the lateral hypothalamic area, the dorsomedial hypothalamic nucleus, and the paraventricular nucleus (PVN), whereas the ventromedial hypothalamic nucleus (VMN) contains only Y1 receptor-positive neurons (60). Furthermore, a study by Chee et al (15) reports that NPY inhibits the excitatory (anorexigenic) outflow between the VMN and ARC POMC neural circuitry via the activation of the Y1 receptor subtype in the VMN.…”

“…NPY affects a wide variety of physiological functions via the activation of a population of distinct G protein-coupled NPY receptor subtypes: Y1, Y2, Y4, and Y5 (29,35). All NPY receptor subtypes are expressed in the hypothalamus (18,60). The effects of NPY on feeding and energy homeostasis are thought to be mediated largely by hypothalamic Y1 and Y5 receptors (reviewed in Ref.…”

NPY Y1 Receptors Differentially Modulate GABAA and NMDA Receptors via Divergent Signal-Transduction Pathways to Reduce Excitability of Amygdala Neurons

“…Y 1 Rs are expressed on both BLA pyramidal and non-pyramidal neurons, where they are postsynaptically localized (Rostkowski et al, 2009;Stanic et al, 2011). A functional interaction between GABAergic and Y 1 Rs mediating transmission was first demonstrated in the cortical region (Kask et al, 1996) and, subsequently, in other brain regions, such as posterior hypothalamus (Naveilhan et al, 2001) and central and medial amygdala (Oberto et al, 2000(Oberto et al, , 2001) of mice.…”