Kainate receptor activation affects GABAergic inhibition in the hippocampus by mechanisms that are thought to involve the GluR5 subunit. We report that disruption of the GluR5 subunit gene does not cause the loss of functional KARs in CA1 interneurons, nor does it prevent kainate-induced inhibition of evoked GABAergic synaptic transmission onto CA1 pyramidal cells. However, KAR function is abolished in mice lacking both GluR5 and GluR6 subunits, indicating that KARs in CA1 stratum radiatum interneurons are heteromeric receptors composed of both subunits. In addition, we show the presence of presynaptic KARs comprising the GluR6 but not the GluR5 subunit that modulate synaptic transmission between inhibitory interneurons. The existence of two separate populations of KARs in hippocampal interneurons adds to the complexity of KAR localization and function.

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BackgroundReactive astrocytes are implicated in the development and maintenance of neuroinflammation in the demyelinating disease multiple sclerosis (MS). The sphingosine kinase 1 (SphK1)/sphingosine1-phosphate (S1P) receptor signaling pathway is involved in modulation of the inflammatory response in many cell types, but the role of S1P receptor subtype 3 (S1P3) signaling and SphK1 in activated rat astrocytes has not been defined.Methodology/Principal FindingsUsing immunohistochemistry we observed the upregulation of S1P3 and SphK1 expression on reactive astrocytes and SphK1 on macrophages in MS lesions. Increased mRNA and protein expression of S1P3 and SphK1, as measured by qPCR and Western blotting respectively, was observed after treatment of rat primary astrocyte cultures with the pro-inflammatory stimulus lipopolysaccharide (LPS). Activation of SphK by LPS stimulation was confirmed by SphK activity assay and was blocked by the use of the SphK inhibitor SKI (2-(p-hydroxyanilino)-4-(p-chlorphenyl) thiazole. Treatment of astrocytes with a selective S1P3 agonist led to increased phosphorylation of extracellular signal-regulated kinase (ERK)-1/2), which was further elevated with a LPS pre-challenge, suggesting that S1P3 upregulation can lead to increased functionality. Moreover, astrocyte migration in a scratch assay was induced by S1P and LPS and this LPS-induced migration was sensitive to inhibition of SphK1, and independent of cell proliferation. In addition, S1P induced secretion of the potentially neuroprotective chemokine CXCL1, which was increased when astrocytes were pre-challenged with LPS. A more prominent role of S1P3 signaling compared to S1P1 signaling was demonstrated by the use of selective S1P3 or S1P1 agonists.Conclusion/SignificanceIn summary, our data demonstrate that the SphK1/S1P3 signaling axis is upregulated when astrocytes are activated by LPS. This signaling pathway appears to play a role in the establishment and maintenance of astrocyte activation. Upregulation of the pathway in MS may be detrimental, e.g. through enhancing astrogliosis, or beneficial through increased remyelination via CXCL1.

Gene-environment interactions are known to play a major role in the ethiopathology of several neuropsychiatric disorders, including Alzheimer's disease (AD). The present study investigates whether environmental manipulations, that is, social isolation, may affect the genetic predisposition to develop AD-related traits in a triple transgenic mouse model (3 x Tg-AD), as suggested by our previous study employing physical exercise (Pietropaolo et al., 2008). Mutant and wild type mice of both sexes were housed singly or in groups from weaning, and evaluated behaviorally at 6 to 7 months of age. Independent of sex, the 3 x Tg-AD genotype was associated with enhanced acoustic startle response, improved performance in the cued version of the water maze and a clear impairment in the Y maze. Notably, the female (but not male) mutant mice showed increased anxiety. Although social isolation was effective in modifying several behaviors, it did not exacerbate any of the AD-like symptoms. Our findings demonstrated the differential susceptibility of the 3 x Tg-AD mouse line to environmental manipulations, showing that social isolation did not induce remarkable effects on the genetically determined AD-like symptoms, in contrast to what previously observed with physical exercise.