Ablation of Sphingosine 1-Phosphate Receptor Subtype 3 Impairs Hippocampal Neuron Excitability In vitro and Spatial Working Memory In vivo

Abstract

Understanding the role of the bioactive lipid mediator sphingosine 1-phosphate (S1P) within the central nervous system has recently gained more and more attention, as it has been connected to major diseases such as multiple sclerosis and Alzheimer's disease. Even though much data about the functions of the five S1P receptors has been collected for other organ systems, we still lack a complete understanding for their specific roles, in particular within the brain. Therefore, it was the aim of this study to further elucidate the role of S1P receptor subtype 3 (S1P3) in vivo and in vitro with a special focus on the hippocampus. Using an S1P3 knock-out mouse model we applied a range of behavioral tests, performed expression studies, and whole cell patch clamp recordings in acute hippocampal slices. We were able to show that S1P3 deficient mice display a significant spatial working memory deficit within the T-maze test, but not in anxiety related tests. Furthermore, S1p3 mRNA was expressed throughout the hippocampal formation. Principal neurons in area CA3 lacking S1P3 showed significantly increased interspike intervals and a significantly decreased input resistance. Upon stimulation with S1P CA3 principal neurons from both wildtype and S1P3−/− mice displayed significantly increased evoked EPSC amplitudes and decay times, whereas rise times remained unchanged. These results suggest a specific involvement of S1P3 for the establishment of spatial working memory and neuronal excitability within the hippocampus.

Optical control of sphingosine-1-phosphate formation and function

“…This is especially useful given that it was recently discovered that GPCRs display sequence selectivity for distinct G protein coupled pathways. 42 Their analysis revealed at least one S1P receptor, S1P 3 (the primary S1P receptor in the nervous system 6 , 43 ), was shown to display a uniquely promiscuous pattern of G protein coupling, which is supported by recent studies of S1P 3 signaling mechanisms in neurons 38 . Unlike our experiments using photoswitchable S1P, substitution of native receptors with a DREADD or a light-activated GPCR would not allow for mechanistic study of the endogenous S1P signaling pathways.…”

Targeting the Sphingosine-1-Phosphate Axis for Developing Non-narcotic Pain Therapeutics

“…On hippocampal slices, it has been shown that S1PR1 signaling influences NMDAR properties [101]. Similarly, ablation of S1PR3 impairs neuronal hippocampal excitability in vitro [102] and reduces inflammatory processes in medial prefrontal cortex in mice [103], both areas involved in pain processing [104]. However, more in-depth studies on S1P signaling also need to be addressed towards other brain structures responsible for pain modulation, such as cingulate cortex, thalamus, periaqueductal grey, and rostroventral medulla.…”

Sphingosine-1-phosphate receptor 3 in the medial prefrontal cortex promotes stress resilience by reducing inflammatory processes

“…Sphingosine-1-phosphate receptor 3 is a G protein-coupled receptor that, upon binding to its ubiquitous ligand sphingosine-1-phosphate (S1P), plays a critical role in regulating multiple cellular processes including inflammation, migration, angiogenesis, differentiation, and proliferation in peripheral tissue 12–19 . Little is known about the function of S1PR3 in the brain, although a role for S1PR3 in spatial working memory and excitability of hippocampal neurons in rodents has been reported 20 . In this study, we identify S1PR3 in the mPFC as a key mediator of resilience to the adverse effects of stress in rats.…”