Galanin Receptor 1 Deletion Exacerbates Hippocampal Neuronal Loss after Systemic Kainate Administration in Mice

Abstract

BackgroundGalanin is a neuropeptide with a wide distribution in the central and peripheral nervous systems and whose physiological effects are mediated through three G protein-coupled receptor subtypes, GalR1, GalR2, and GalR3. Several lines of evidence indicate that galanin, as well as activation of the GalR1 receptor, is a potent and effective modulator of neuronal excitability in the hippocampus.Methodology/Principal FindingsIn order to test more formally the potential influence of GalR1 on seizure-induced excitotoxic cell death, we conducted functional complementation tests in which transgenic mice that exhibit decreased expression of the GalR1 candidate mRNA underwent kainate-induced status epilepticus to determine if the quantitative trait of susceptibility to seizure-induced cell death is determined by the activity of GalR1. In the present study, we report that reduction of GalR1 mRNA via null mutation or injection of the GalR1 antagonist, galantide, prior to kainate-induced status epilepticus induces hippocampal damage in a mouse strain known to be highly resistant to kainate-induced neuronal injury. Wild-type and GalR1 knockout mice were subjected to systemic kainate administration. Seven days later, Nissl and NeuN immune- staining demonstrated that hippocampal cell death was significantly increased in GalR1 knockout strains and in animals injected with the GalR1 antagonist. Compared to GalR1-expressing mice, GalR1-deficient mice had significantly larger hippocampal lesions after status epilepticus.Conclusions/SignificanceOur results suggest that a reduction of GalR1 expression in the C57BL/6J mouse strain renders them susceptible to excitotoxic injury following systemic kainate administration. From these results, GalR1 protein emerges as a new molecular target that may have a potential therapeutic value in modulating seizure-induced cell death.

The Effects of Kainic Acid-Induced Seizure on Gene Expression of Brain Neurotransmitter Receptors in Mice Using RT2 PCR Array

“…Also, it was reported that both GalR1 and GALR2 could mediate anticonvulsant effects of galanin (Mazarati & Lu, 2005). Similar to this study, GALR1 deficiency could influence susceptibility to KA-induced injury in C57BL/6J mice (Schauwecker, 2010). …”

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

“…Increased neuronal loss in hippocampus after kainic acid administration (Schauwecker, 2010 (Brunner et al, 2014) Double GAL 1 Â GAL 2 -KO (Jacoby et al, 2002) Â Deltagen (San Carlos, CA)/C57BL/6J Â (129 ⁄ Svx C57BL/6) Galanin had no effect on GABAergic IPSPs in CeA neurons (decreased in WT) (Bajo et al, 2012) ACh, acetylcholine; bp, base pairs; CGRP, calcitonin gene-related peptide; CPZ, cuprizone; DBH, dopamine b-hydroxylase; EGFP, green fluorescent protein; GH, growth hormone; GI, gastrointestinal; Hbg, human b-globulin; IGF, insulin-like growth factor; lacZ, b-galactosidase; PDGF, platelet-derived growth factor; PSNI, partial saphenous nerve ligation injury; PVN, paraventricular nucleus of the hypothalamus; SNL, spinal nerve ligation. 126 2011, 2012), chronic constriction nerve injury (Nahin et al, 1994), orofacial pain (Tokunaga et al, 1992), exercise (Legakis et al, 2000), electroconvulsive stimulation (Christiansen, 2011), and herpes simplex virus infection (Henken and Martin, 1992).…”

Kainic Acid-Induced Neuronal Degeneration in Hippocampal Pyramidal Neurons Is Driven by Both Intrinsic and Extrinsic Factors: Analysis of FVB/N↔C57BL/6 Chimeras

“…Schauwecker's group has explored this hypothesis but has found no compelling evidence in this regard (Schauwecker, 2003a(Schauwecker, ,b, 2010b. However, another receptor family, the galanin receptors, has been found to have an intriguing role in hippocampal development and plasticity (Burazin et al, 2000) and several lines of evidence (although the data are somewhat contradictory) support a role for the galanin receptor 1 (GalR1) in neuroprotection in status epilepticus (Mazarati et al, 2004;Schauwecker, 2010a). First, Schauwecker and colleagues (Schauwecker et al, 2004) found a distal region on chromosome 18, that includes the GalR1 locus, houses a quantitative trait locus that significantly influences susceptibility to kainic acid-induced cell death (called,Sicd1).…”

“…This region was further refined using FVB.B6-Sicd1 lines of mice and the GalR1 locus remained with the region (Lorenzana et al, 2007). Second, recent evidence has demonstrated that GalR1 mRNA is differentially expressed in the hippocampus of sensitive (FVB) and resistant (B6) strains under baseline conditions (Kong et al, 2008;Schauwecker, 2010a). Third, Schauwecker (2010a) provided more direct evidence for the protective role of GalR1 by injecting an antagonist of GalR1 which resulted in increased cell death in the hippocampus following KA in the resistant B6 strain.…”

“…Third, Schauwecker (2010a) provided more direct evidence for the protective role of GalR1 by injecting an antagonist of GalR1 which resulted in increased cell death in the hippocampus following KA in the resistant B6 strain. However, examination of GalR1 KO mice has given conflicting results with both decreased protection in the KO (Schauwecker, 2010a) or no difference between KO and wild-type in KA sensitivity (Mazarati et al, 2004). The differences in these two studies may be due to the number of backcrosses to the B6 mouse which would result in differences in the extent of the B6 background strain in the KO.…”