GPR68 deletion impairs hippocampal long-term potentiation and passive avoidance behavior
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GPR68 deletion impairs hippocampal long‑term potentiation and passive avoidance behavior Yuanyuan Xu, Mike T. Lin and Xiang‑ming Zha*
Abstract Increased neural activities reduced pH at the synaptic cleft and interstitial spaces. Recent studies have shown that protons function as a neurotransmitter. However, it remains unclear whether protons signal through a metabotropic receptor to regulate synaptic function. Here, we showed that GPR68, a proton-sensitive GPCR, exhibited wide expres‑ sion in the hippocampus, with higher expression observed in CA3 pyramidal neurons and dentate granule cells. In organotypic hippocampal slice neurons, ectopically expressed GPR68-GFP was present in dendrites, dendritic spines, and axons. Recordings in hippocampal slices isolated from GPR68−/− mice showed a reduced fiber volley at the Schaffer collateral-CA1 synapses, a reduced long-term potentiation (LTP), but unaltered paired-pulse ratio. In a stepthrough passive avoidance test, GPR68−/− mice exhibited reduced avoidance to the dark chamber. These findings showed that GPR68 contributes to hippocampal LTP and aversive fear memory. Keywords: OGR1, Synaptic plasticity, Fear memory Brain acidification occurs in both physiological and disease conditions. A better understanding of how protons regulate synaptic physiology will help advancing our knowledge of brain physiology and pathophysiology. However, it remains unclear whether protons signal through metabotropic receptors to alter synaptic function. GPR68 (also known as OGR1-ovarian cancer G protein-coupled receptor 1) is a proton-sensitive GPCR expressed in brain neurons. GPR68 starts to get activated at about pH 7.4, reaches maximal activation at ~ 6.8–6.5, and primarily couples to Gq/11 to elicit intracellular phospholipase C/calcium signaling [1–3]. Several histidine residues are important for its proton sensing [2]. Potentiating GPR68 function in mice alters fear memory [4]. These studies suggest a potential role of GPR68 in synaptic function. *Correspondence: [email protected] Department of Physiology and Cell Biology, University of South Alabama College of Medicine, 5851 USA Dr. N, MSB3074, Mobile, AL 36688, USA
To determine whether GPR68 contributes to synaptic physiology, we started by examining the expression of GPR68 in hippocampus. Since there are no reliable antibodies to detect endogenous GPR68 (as controlled by GPR68−/− tissue, not shown), we utilized a Tg(Gpr68eGFP) mouse line which expresses GFP under the control of Gpr68 promoter [5]. Thus, in this transgenic mouse, expression pattern of GFP reflects that of GPR68 in vivo. We performed cryosections of brains isolated from wildtype (WT, negative control for GFP staining) and the Tg(Gpr68-eGFP) mice, and stained the sections using a GFP antibody (see Additional File 1 for detailed methods for all experiments). Within the hippocampus, dentate granule cells and CA3 pyramidal neurons exhibited higher expression while CA1 pyramidal neurons exhibited lower staining (Fig. 1a). This expressio
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