Altered synaptic phospholipid signaling in PRG-1 deficient mice induces exploratory behavior and motor hyperactivity resembling psychiatric disorders.

Plasticity related gene 1 (PRG-1) is a neuron specific membrane protein located at the postsynaptic density of glutamatergic synapses. PRG-1 modulates signaling pathways of phosphorylated lipid substrates such as lysophosphatidic acid (LPA). Deletion of PRG-1 increases presynaptic glutamate release probability leading to neuronal over-excitation. However, due to its cortical expression, PRG-1 deficiency leading to increased glutamatergic transmission is supposed to also affect motor pathways. We therefore analyzed the effects of PRG-1 function on exploratory and motor behavior using homozygous PRG-1 knockout (PRG-1-/-) mice and PRG-1/LPA2-receptor double knockout (PRG-1-/-/LPA2-/-) mice in two open field settings of different size and assessing motor behavior in the Rota Rod test. PRG-1-/- mice displayed significantly longer path lengths and higher running speed in both open field conditions. In addition, PRG-1-/- mice spent significantly longer time in the larger open field and displayed rearing and self-grooming behavior. Furthermore PRG-1-/- mice displayed stereotypical behavior resembling phenotypes of psychiatric disorders in the smaller sized open field arena. Altogether, this behavior is similar to the stereotypical behavior observed in animal models for psychiatric disease of autistic spectrum disorders which reflects a disrupted balance between glutamatergic and GABAergic synapses. These differences indicate an altered excitation/inhibition balance in neuronal circuits in PRG-1-/- mice as recently shown in the somatosensory cortex [38]. In contrast, PRG-1-/-/LPA2-/- did not show significant changes in behavior in the open field suggesting that these specific alterations were abolished when the LPA2-receptor was lacking. Our findings indicate that PRG-1 deficiency led to over-excitability caused by an altered LPA/LPA2-R signaling inducing a behavioral phenotype typically observed in animal models for psychiatric disorders.

Plasticity-Related Gene 1 Affects Mouse Barrel Cortex Function via Strengthening of Glutamatergic Thalamocortical Transmission.

Plasticity-related gene-1 (PRG-1) is a brain-specific protein that modulates glutamatergic synaptic transmission. Here we investigated the functional role of PRG-1 in adolescent and adult mouse barrel cortex both in vitro and in vivo. Compared with wild-type (WT) animals, PRG-1-deficient (KO) mice showed specific behavioral deficits in tests assessing sensorimotor integration and whisker-based sensory discrimination as shown in the beam balance/walking test and sandpaper tactile discrimination test, respectively. At P25-31, spontaneous network activity in the barrel cortex in vivo was higher in KO mice compared with WT littermates, but not at P16-19. At P16-19, sensory evoked cortical responses in vivo elicited by single whisker stimulation were comparable in KO and WT mice. In contrast, at P25-31 evoked responses were smaller in amplitude and longer in duration in WT animals, whereas KO mice revealed no such developmental changes. In thalamocortical slices from KO mice, spontaneous activity was increased already at P16-19, and glutamatergic thalamocortical inputs to Layer 4 spiny stellate neurons were potentiated. We conclude that genetic ablation of PRG-1 modulates already at P16-19 spontaneous and evoked excitability of the barrel cortex, including enhancement of thalamocortical glutamatergic inputs to Layer 4, which distorts sensory processing in adulthood.

Effects of radiofrequency electromagnetic fields (UMTS) on reproduction and development of mice: a multi-generation study.

Male and female mice (C57BL) were chronically exposed (life-long, 24 h/day) to mobile phone communication electromagnetic fields at approximately 1966 MHz (UMTS). Their development and fertility were monitored over four generations by investigating histological, physiological, reproductive and behavioral functions. The mean whole-body SARs, calculated for adult animals at the time of mating, were 0 (sham), 0.08, 0.4 and 1.3 W/kg. Power densities were kept constant for each group (0, 1.35, 6.8 and 22 W/m(2)), resulting in varying SARs due to the different numbers of adults and pups over the course of the experiment. The experiment was done in a blind fashion. The results show no harmful effects of exposure on the fertility and development of the animals. The number and the development of pups were not affected by exposure. Some data, albeit without a clear dose-response relationship, indicate effects of exposure on food consumption that is in accordance with some data published previously. In summary, the results of this study do not indicate harmful effects of long-term exposure of mice to UMTS over several generations.

Lymphoma development in mice chronically exposed to UMTS-modulated radiofrequency electromagnetic fields.

There are public concerns regarding possible carcinogenic or cancer-promoting effects of electromagnetic fields (EMFs) from mobile phones and base stations. The objective of the present study was to investigate whether chronic exposure to EMFs of the UMTS (Universal Mobile Telecommunication System) influences the development of lymphoma in a lymphoma animal model, the AKR/J mouse. Unrestrained mice were chronically sham-exposed (n = 160) or exposed (n = 160) in identical exposure systems (radial waveguides) to a generic UMTS test signal (24 h per day, 7 days per week, 0.4 W/kg SAR). Additionally, 30 animals were kept as cage controls. Animals were checked visually each day and were weighed and palpated weekly to detect swollen lymph nodes. Starting at the age of 6 months, blood samples were taken from the tail every 2 weeks to perform differential leukocyte counts and to measure the hematocrit. Visibly diseased animals or those older than 43 weeks were killed humanely, and tissue slices were examined for metastatic infiltrations and lymphoma type. The study was performed in a blinded way. Cage control animals had a significantly lower growth rate than those kept in the radial waveguides. The number of ill animals, the mean survival time, and the severity code of the disease did not differ between the experimental groups. Therefore, the data show no negative effects from exposure and corroborate earlier findings in AKR/J mice exposed to GSM EMF (Sommer et al., BMC Cancer 4, 77-90, 2004).

Cognitive function in outbred house mice after 22 weeks of drinking oxygenated water.

Oxygen-enriched drinking water, which is increasingly sold worldwide, is claimed to "keep both the body and the mind healthy." However, currently there is no scientific evidence for such a statement. Therefore, we assessed the effect of 22 weeks of drinking oxygenated water on cognitive performance in healthy mice, using a spatial learning task and behavioral observations. Thirty-six female mice (age 3 to 6 months) received either hyperoxic or normal tap water (approximately 6.6 vs. 1.8 microg O(2) g(-1) day(-1), respectively) throughout the study period. Mice were weighed one to two times per month, and a blood sample was taken from the tail to determine the hematocrit. In addition, red blood cells were counted microscopically one and two months after the start of the experiment. Four weeks after the last blood sample (21 weeks after the start of the experiment), exploration behavior and locomotor activity were observed on a holeboard, and learning ability tests were performed using an elevated open maze. No significant differences were seen between groups for any of the parameters investigated. Thus, the study does not support the hypothesis that drinking oxygenated water improves cognitive function or hematological parameters in mice.

50 Hz magnetic fields of 1 mT do not promote lymphoma development in AKR/J mice.

Some epidemiological studies suggest that exposure to power-frequency magnetic fields increases the risk of leukemia, especially in children with high residential exposures. In contrast, most animal studies did not find a correlation between magnetic-field exposure and hematopoietic diseases. The present study was performed to investigate whether chronic, high-level (1 mT) magnetic-field exposure had an influence on lymphoma development in a mouse strain that is genetically predisposed to thymic lymphoblastic lymphoma. Three groups of 160 unrestrained female AKR/J mice were sham-exposed or exposed to sinusoidal 50 Hz magnetic fields beginning at the age of 12 weeks for 32 weeks, 7 days per week, either for 24 h per day or only during nighttime (12 h). Exposure was carried out in a blind design. Exposure did not affect survival time, body weight, lymphoma development or hematological parameters. The resulting data do not support the hypothesis that exposure to sinusoidal 50 Hz magnetic fields is a significant risk factor for hematopoietic diseases, even at this relatively high exposure level.

No effects of GSM-modulated 900 MHz electromagnetic fields on survival rate and spontaneous development of lymphoma in female AKR/J mice.

BACKGROUND: Several reports indicated that non-thermal electromagnetic radiation such as from mobile phones and base stations may promote cancer. Therefore, it was investigated experimentally, whether 900 MHz electromagnetic field exposure influences lymphoma development in a mouse strain that is genetically predisposed to this disease. The AKR/J mice genome carries the AK-virus, which leads within one year to spontaneous development of thymic lymphoblastic lymphoma. METHODS: 320 unrestrained female mice were sham-exposed or exposed (each n = 160 animals) to GSM like 900 MHz electromagnetic fields for 24 hours per day, 7 days per week, at an average whole body specific absorption rate (SAR) value of 0.4 W/kg. Animals were visually checked daily and were weighed and palpated weekly. Starting with an age of 6 months, blood samples were taken monthly from the tail. Animals with signs of disease or with an age of about 46 weeks were sacrificed and a gross necropsy was performed. RESULTS: Electromagnetic field exposure had a significant effect on body weight gain, with higher values in exposed than in sham-exposed animals. However, survival rate and lymphoma incidence did not differ between exposed and sham-exposed mice. CONCLUSION: These data do not support the hypothesis that exposure to 900 MHz electromagnetic fields is a significant risk factor for developing lymphoma in a genetically predisposed species, even at a relatively high exposure level.

The risk of lymphoma in AKR/J mice does not rise with chronic exposure to 50 Hz magnetic fields (1 microT and 100 microT).

Some epidemiological studies suggest that exposure to 50 or 60 Hz magnetic fields might increase the risk of leukemia, especially in children with a comparable high residential exposure. To investigate this possibility experimentally, the influence of 50 Hz magnetic-field exposure on lymphoma induction was determined in a mouse strain that is genetically predisposed to this disease. The AKR/J mouse genome carries the AK virus, which leads within 1 year to spontaneous development of thymic lymphoblastic lymphoma. Beginning at an age of 4-5 weeks, groups of 160 female mice were sham-exposed or exposed to 50 Hz magnetic fields at 1 or 100 microT for 24 h per day, 7 days per week, for 38 weeks. Animals were checked visually daily and were weighed and palpated weekly. There was no effect of magnetic-field exposure on body weight gain or survival rate, and lymphoma incidence did not differ between exposed and sham-exposed animals. Therefore, these data do not support the hypothesis that chronic exposure to 50 Hz magnetic fields is a significant risk factor for developing hematopoietic malignancy.

Seasonality of energetic functioning and production of reactive oxygen species by lugworm (Arenicola marina) mitochondria exposed to acute temperature changes.

The influence of seasonal and acute temperature changes on mitochondrial functions were studied in isolated mitochondria of the eurythermal lugworm Arenicola marina (Polychaeta), with special emphasis on the interdependence of membrane potential and radical production. Acclimatisation of lugworms to pre-spawning/summer conditions is associated with rising mitochondrial substrate oxidation rates, higher proton leakage rates, elevated membrane potentials, and increased production of reactive oxygen species (ROS) in isolated mitochondria, compared with mitochondria from winter animals. However, a high ROS production was compensated for by higher activities of the antioxidant enzymes catalase and superoxide dismutase, as well as lower mitochondrial densities in summer compared with winter animals. In summer animals, a higher sensitivity of the proton leakage rate to changes of membrane potential will confer better flexibility for metabolic regulation (mild uncoupling) in response to temperature change. These seasonal alterations in mitochondrial functions suggest modifications of energy metabolism in eurythermal and euryoxic organisms on intertidal mudflats during summer. In winter, low and less changeable temperatures in intertidal sedimentary environments permit higher respiratory efficiency at low aerobic metabolic rates and lower membrane potentials in A. marina mitochondria.