A20/TNFAIP3 heterozygosity predisposes to behavioral symptoms in a mouse model for neuropsychiatric lupus.

Background: Neuropsychiatric lupus (NPSLE) refers to the neurological and psychiatric manifestations that are commonly observed in patients with systemic lupus erythematosus (SLE). An important question regarding the pathogenesis of NPSLE is whether the symptoms are caused primarily by CNS-intrinsic mechanisms or develop as a consequence of systemic autoimmunity. Currently used spontaneous mouse models for SLE have already contributed significantly to unraveling how systemic immunity affects the CNS. However, they are less suited when interested in CNS primary mechanisms. In addition, none of these models are based on genes that are associated with SLE. In this study, we evaluate the influence of A20, a well-known susceptibility locus for SLE, on behavior and CNS-associated changes in inflammatory markers. Furthermore, given the importance of environmental triggers for disease onset and progression, the influence of an acute immunological challenge was evaluated. Methods: Female and male A20 heterozygous mice (A20+/-) and wildtype littermates were tested in an extensive behavioral battery. This was done at the age of 10±2weeks and 24 â€‹± â€‹2 weeks to evaluate the impact of aging. To investigate the contribution of an acute immunological challenge, LPS was injected intracerebroventricularly at the age of 10±2weeks followed by behavioral analysis. Underlying molecular mechanisms were evaluated in gene expression assays on hippocampus and cortex. White blood cell count and blood-brain barrier permeability were analyzed to determine whether peripheral inflammation is a relevant factor. Results: A20 heterozygosity predisposes to cognitive symptoms that were observed at the age of 10 â€‹± â€‹2 weeks and 24 â€‹± â€‹2 weeks. Young A20+/- males and females showed a subtle cognitive phenotype (10±2weeks) with distinct neuroinflammatory phenotypes. Aging was associated with clear neuroinflammation in female A20+/- mice only. The genetic predisposition in combination with an environmental stimulus exacerbates the behavioral impairments related to anxiety, cognitive dysfunction and sensorimotor gating. This was predominantly observed in females. Furthermore, signs of neuroinflammation were solely observed in female A20+/- mice. All above observations were made in the absence of peripheral inflammation and of changes in blood-brain barrier permeability, thus consistent with the CNS-primary hypothesis. Conclusions: We show that A20 heterozygosity is a predisposing factor for NPSLE. Further mechanistic insight and possible therapeutic interventions can be studied in this mouse model that recapitulates several key hallmarks of the disease.

Improved spatial learning is associated with increased hippocampal but not prefrontal long-term potentiation in mGluR4 knockout mice.

Although much information about metabotropic glutamate receptors (mGluRs) and their role in normal and pathologic brain function has been accumulated during the last decades, the role of group III mGluRs is still scarcely documented. Here, we examined mGluR4 knockout mice for types of behavior and synaptic plasticity that depend on either the hippocampus or the prefrontal cortex (PFC). We found improved spatial short- and long-term memory in the radial arm maze, which was accompanied by enhanced long-term potentiation (LTP) in hippocampal CA1 region. In contrast, LTP in the PFC was unchanged when compared with wild-type controls. Changes in paired-pulse facilitation that became overt in the presence of the GABAA antagonist picrotoxin indicated a function of mGluR4 in maintaining the excitation/inhibition balance, which is of crucial importance for information processing in the brain and the deterioration of these processes in neuropsychological disorders such as autism, epilepsy and schizophrenia.

LPA5 receptor plays a role in pain sensitivity, emotional exploration and reversal learning.

Lysophosphatidic acid (LPA) is a bioactive lipid acting on the nervous system through at least 6 different G protein-coupled receptors. In this study, we examined mice lacking the LPA5 receptor using an extensive battery of behavioral tests. LPA5-deficient mice showed decreased pain sensitivity in tail withdrawal, faster recovery in one inflammatory pain procedure (complete Freund's adjuvant-induced inflammation) and attenuated responses under specific neuropathic pain conditions. Notably, deletion of LPA5 also induced nocturnal hyperactivity and reduced anxiety in the mutant mice. Several exploratory tasks revealed signs of reduced anxiety in LPA5 knockout mice including increased visits to the arena center and reduced thigmotaxis in the open field, and more open arm entries in the elevated plus maze. Finally, LPA5 knockout mice also displayed marked reduction in social exploration, although several other tests indicated that these mice were able to respond normally to environmental stimuli. While learning and memory performance was not impaired in LPA5-deficient mice, we found differences, e.g., targeted swim strategy and reversal learning, as well as scheduled appetitive conditioning that might indicate differential motivational behavior. These results imply that LPA5 might be involved in both nociception and mechanisms of pain hypersensitivity, as well as in anxiety-related and motivational behaviors. These observations further support the proposed involvement of LPA signaling in psychopathology.

Influence of intensive physical training on urinary nitrate elimination and plasma endothelin-1 levels in patients with congestive heart failure.

BACKGROUND: Congestive heart failure (CHF) is associated with increased peripheral vascular resistance. Exercise-induced shear stress may release endothelial relaxing factors, such as nitric oxide (NO), and inhibit the production of vasoconstrictors such as endothelin-1 (ET-1) thereby modulating vascular tone. We examined the effect of intensive training on ET-1 plasma concentrations and NO-metabolite elimination in patients with CHF after acute myocardial infarction. METHODS: Seventeen patients with CHF after a myocardial infarction were randomized to an exercise group (n = 9), who performed physical training for 8 weeks, or a control group (n = 8) who received usual care. A physical examination, pulmonary function test, and a maximum exercise test were performed, and 24-hour urinary nitrate elimination and ET-1 in plasma were determined before and at the end of the study period. RESULTS: Maximal oxygen uptake remained unchanged in controls (17.9 +/- 1.4 to 18.1 +/- 1.5 mL/(kg min) but increased in the exercise group (from 20.4 +/- 0.75 to 26.7 +/- 1.4 mL/(kg min). After 8 weeks the urinary nitrate elimination in controls was significantly decreased (1.25 +/- 0.20 to 1.03 +/- 0.22 mmol/24 hours; P < 0.001), while it was unchanged in the exercise group (1.26 +/- 0.23 to 1.39 +/- 0.28; P = 0.71). Plasma ET-1 levels did not change after 8 weeks (7.87 +/- 0.62 versus 7.57 +/- 0.75 and 7.13 +/- 0.6 versus 7.35 +/- 0.7 pg/mL for control and exercise groups, respectively). CONCLUSION: In patients with CHF after acute myocardial infarction nitrate elimination decreases over the subsequent 2 months. This trend was reversed by training. Because nitrate elimination mirrors endogenous NO production, these results suggest that training may positively influence endothelial vasodilator function.