Phenotypic analysis of GalR2 knockout mice in anxiety- and depression-related behavioral tests

Abstract

Neuropeptide galanin modulates a variety of central nervous system functions by signaling through three G-protein-coupled receptor subtypes, GalR1 through GalR3. Galanin and its receptors are expressed at high levels in the limbic structures of the rodent brain. Intracerebroventricular injection of galanin has been shown to modulate depression and anxiety-like behaviors in the rat. We have previously shown that chronic antidepressant treatments increase the binding of a GalR2-preferring ligand, galanin (2-11), to the dorsal raphe nucleus (DRN) of the rat, which, along with the finding that intra-DRN infusion of galanin (2-11) increases the release of serotonin in the hippocampus, suggests that GalR2 signaling might exert antidepressant-like actions by modulating ascending serotonergic outflow. Recently, two research groups reported their phenotypic analysis of a GalR2 knockout (GalR2KO) mouse line, produced by gene-trapping method and maintained on a 129S1/SvImJ genetic background. The only positive finding in that GalR2KO mouse line was an anxiogenic-like phenotype specific to the elevated plus-maze. Because it is known that genetic background can affect the outcome of behavioral tests, in the present study, we analyzed a separate GalR2KO line, which was produced by targeted deletion and maintained on a C57BL/6 background, using a different set of depression- and anxiety-related tests. GalR2KO mice exhibited a more persistent depressive-like phenotype in the learned helplessness paradigm as well as increased immobility in the tail suspension test when results from the present studies were combined by fixed effect meta-analysis with that reported by Gottsch and colleagues. GalR2KO mutants showed anxiety-like behavior comparable to wild-type littermates in the elevated plus-maze, open-field, and light-dark transfer tests. The present findings are consistent with a predicted antidepressant-like effect of GalR2 signaling, suggesting that GalR2 might be a valid drug target for depressive disorders.

GAL 3 receptor KO mice exhibit an anxiety-like phenotype

“…Consistent with an antidepressant-like effect of GAL 2 receptor signaling (14), Lu et al (15) observed a depressive-like phenotype in GAL 2 receptor-deficient (GAL 2 -KO) mice but found no GAL 2 receptor-mediated effects on anxiety-related behavior. GAL 3 receptor stimulation was suggested to induce a depression-like profile because decreased immobility and increased swimming in the rat FST were observed after treatment with the nonpeptidergic GAL 3 receptor-selective antagonist 1-phenyl-3-[[3-(trifluoromethyl)phenyl]imino]-1H-indol-2-one (SNAP 37889).…”

“…These contradictory results may be attributed to the differential actions of the three GAL receptor subtypes (34). Whereas stimulation of the GAL 2 receptor seems to be responsible for antidepressant-like effects (15,39,40), the inhibitory receptor subtypes GAL 1 (41) and GAL 3 seem to contribute to the prodepressive effects of GAL (42). Thus, in addition to its anxiolytic effect, the GAL 3 receptor antagonist SNAP 37889 exerts an antidepressant-like activity in rats (16).…”

Physiology, Signaling, and Pharmacology of Galanin Peptides and Receptors: Three Decades of Emerging Diversity

“…Galanin has been linked to the regulation of metabolic and osmotic homeostasis (Crawley, 1999;Landry et al, 2000;Gundlach, 2002), reproduction (Rossmanith et al, 1996;Gundlach, 2002), nociception (Liu and Hökfelt, 2002), arousal/sleep (Sherin et al, 1998;Steininger et al, 2001), and cognition (McDonald et al, 1998;Kinney et al, 2002), and these functions have been subsequently linked to the actions of specific galanin receptors. For example, GAL 1 has been linked strongly with the CNS and PNS and with modulatory actions on neurotransmission and anxiety, reward, and nociception (see details below), whereas GAL 2 is more broadly expressed and in the CNS is implicated in neurodevelopment (Burazin et al, 2000), modulation of both neurotransmission and affective behaviors (Karlsson and Holmes, 2006;Lu et al, 2008), neurite outgrowth in normal hippocampus (Elliott-Hunt et al, 2004), and neuronal survival and neurogenesis in injured hippocampus (Elliott-Hunt et al, 2004;Mazarati et al, 2004;Pirondi et al, 2005a) (see details below). Galanin and galanin receptors have more recently been associated with neurogenesis and embryonic and adult neural stem cells (see section VIII).…”

“…Despite their development by two laboratories (Gottsch et al, 2005;Hobson et al, 2006;Lu et al, 2008), the profile of GAL 2 -KO mice in terms of seizures and epilepsy has not be reported. In contrast, overexpression of galanin in seizure pathways, using both transgenic and virus vector transfection methods, retards the epileptic process.…”

Epilepsia y actividad física: conceptos desde la perspectiva de las ciencias básicas

“…Los investigadores relacionan los efectos positivos inducidos por el ejercicio con el incremento de la galanina. Este es un neuropéptido que tiene efectos antidepresivos y anticonvulsivantes (79)(80)(81)(82)(83).…”