AMPA receptor subunit 1 (GluR-A) knockout mice model the glutamate hypothesis of depression.

Recent evidence indicates that glutamate homeostasis and neurotransmission are altered in major depressive disorder, but the nature of the disruption and the mechanisms by which it contributes to the syndrome are unclear. Glutamate can act via AMPA, NMDA, or metabotropic receptors. Using targeted mutagenesis, we demonstrate here that mice with deletion of the main AMPA receptor subunit GluR-A represent a depression model with good face and construct validity, showing behavioral and neurochemical features of depression also postulated for human patients. GluR-A(-/-) mice display increased learned helplessness, decreased serotonin and norepinephrine levels, and disturbed glutamate homeostasis with increased glutamate levels and increased NMDA receptor expression. These results correspond well with current concepts regarding the role of AMPA and NMDA receptors in depression, postulating that compounds that augment AMPA receptor signaling or decrease NMDA receptor functions have antidepressant effects. GluR-A(-/-) mice represent a model to investigate the pathophysiology underlying the depressive phenotype and to identify changes in neural plasticity and resilience evoked by the genetic alterations in glutamatergic function. Furthermore, GluR-A(-/-) mice may be a valuable tool to study biological mechanisms of AMPA receptor modulators and the efficacy of NMDA antagonists in reducing behavioral or biochemical changes that correlate with increased helplessness.

Maternal stress during pregnancy induces depressive-like behavior only in female offspring and correlates to their hippocampal Avp and Oxt receptor expression.

The majority of studies examining the consequences of prenatal stress in rodent models analyze pups having been raised by their biological mother, i.e. the female which experienced stress during her pregnancy. To test whether pregnancy stress changes maternal behavior and thereby - in addition to stress exposure in utero - influences behavior and brain function of offspring, we implemented a fostering model, in which mouse pups that were not stressed in utero, are raised by dams which were exposed to stress during their pregnancy. We found that dams, which were stressed during pregnancy (PS foster dams), unexpectedly displayed slightly more active and passive light time nursing compared to unstressed dams (CON foster dams). Adult male offspring which were raised by a PS foster dam showed significantly less anxiety-like behavior compared to males raised by a CON foster dam, whereas adult female offspring which were raised by PS foster dams displayed increased depressive-like behavior as a tendency. Since the arginine vasopressin receptor 1a (AvpR1a) and the structurally related oxytocin receptor (OxtR) are both closely related to stress-responsiveness, anxiety and depression, mRNA expression of these genes were assessed in the hippocampus of adult male and female offspring. No significant differences in mRNA expression of both receptor types were observed, however, in female offspring of PS foster dams maternal licking/grooming correlated positively with AvpR1a and negatively with OxtR mRNA expression. These findings indicate that stress during pregnancy does not reduce, but slightly increase maternal behavior, which might lead to sex-specific behavioral outcomes and changes in hippocampal AvpR1a and OxtR mRNA expression in adult offspring.

The scent of stress: environmental challenge in the peripartum environment of mice affects emotional behaviours of the adult offspring in a sex-specific manner.

Early adverse experiences are known to influence the risk of developing psychiatric disorders later. To shed further light on the development of laboratory mice, we systematically examined the influence of a prenatal or postnatal olfactory stressor, namely unfamiliar male mouse faeces, presented to pregnant or nursing mouse dams. Maternal and offspring behaviours were then examined. Maternal behaviours relative to controls revealed changes in nest building by the pregnant dams exposed to the unfamiliar faeces. There were no differences among groups on pup retrieval or exploration by the dams. Behavioural phenotyping of male and female offspring as adults included measures of exploration, anxiety, social and depressive-like behaviours. Additionally, serum corticosterone was assessed as a marker of physiological stress response. Group differences were dependent on the sex of the adult offspring. Males raised by dams that were stressed during pregnancy presented elevated emotionality as indicated by increased numbers of faecal boluses in the open field paradigm. Consistent with the effects of prenatal stress on the males only the prenatally stressed females had higher body weights than their respective controls. Indeed, males in both experimental groups had higher circulating corticosterone levels. By contrast, female offspring of dams exposed to the olfactory stressor after parturition were more anxious in the O-maze as indicated by increased latencies in entering the exposed areas of the maze. These findings emphasize the necessity for researchers to consider the pre- and postnatal environments, even of mice with almost identical genetic backgrounds, in designing experiments and interpreting their data.

Morc1 knockout evokes a depression-like phenotype in mice.

Morc1 gene has recently been identified by a DNA methylation and genome-wide association study as a candidate gene for major depressive disorder related to early life stress in rodents, primates and humans. So far, no transgenic animal model has been established to validate these findings on a behavioral level. In the present study, we examined the effects of a Morc1 loss of function mutation in female C57BL/6N mice on behavioral correlates of mood disorders like the Forced Swim Test, the Learned Helplessness Paradigm, O-Maze and Dark-Light-Box. We could show that Morc1(-/-) mice display increased depressive-like behavior whereas no behavioral abnormalities regarding locomotor activity or anxiety-like behavior were detectable. CORT plasma levels did not differ significantly between Morc1(-/-) mice and their wildtype littermates, yet - surprisingly - total Bdnf mRNA-levels in the hippocampus were up-regulated in Morc1(-/-) animals. Although further work would be clarifying, Morc1(-/-) mice seem to be a promising epigenetically validated mouse model for depression associated with early life stress.

Depression-prone mice with reduced glucocorticoid receptor expression display an altered stress-dependent regulation of brain-derived neurotrophic factor and activity-regulated cytoskeleton-associated protein.

Increasing evidence suggests that depression is characterised by impaired brain plasticity that might originate from the interaction between genetic and environmental risk factors. Hence, the aim of this study was to investigate changes in neuroplasticity following exposure to stress, an environmental condition highly relevant to psychiatric disorders, in glucocorticoid receptor-deficient mice (GR(+/-)), a genetic model of predisposition to depression. Specifically, we have analysed the neurotrophin brain-derived neurotrophic factor (BDNF) and the immediate-early gene activity-regulated cytoskeletal-associated protein (Arc), two closely related molecules that can contribute to neuroplastic and morphological changes observed in depression. We found a region-specific influence of the GR-genotype on BDNF levels both under basal and stress conditions. Steady-state levels of BDNF mRNA were unchanged in hippocampus while up-regulated in frontal lobe of GR(+/-) mice. Following exposure to an acute stress, increased processing from pro- to mature BDNF was observed in hippocampal synaptosomes of wild-type mice, but not in GR mutants. Furthermore, the stress-dependent modulation of Arc was impaired in the hippocampus of GR(+/-) mice. These results indicate that GR(+/-) mice show overt differences in the stress-induced modulation of neuroplastic proteins, which may contribute to pathologic conditions that may originate following gene x environment interaction.

Suitability of tamoxifen-induced mutagenesis for behavioral phenotyping.

Tamoxifen-induced mutagenesis via the so-called CreER(T2) fusion enzyme is a key technology for the inducible gene knockout in the adult murine brain. However, it requires a subchronic transient treatment with high doses of the non-selective estrogen receptor antagonist tamoxifen. It has been shown earlier that acute tamoxifen treatment causes behavioral alterations, while the long-term behavioral effects of tamoxifen in mice are so far unknown. Therefore C57BL/6 male mice, a common strain used for targeted mutagenesis and behavioral analyses, were subjected to a tamoxifen treatment protocol as used for inducible mutagenesis in vivo, and analyzed for effects on general behavior (locomotion, exploration), emotional behavior (anxiety, depression) and on learning and memory after a drug-free interval period of 4 weeks. The results demonstrate that a test for depression-like behavior, i.e. the Forced Swim Test, is affected even more than 4 weeks after tamoxifen treatment. In contrast, in all other tests, tamoxifen treated mice showed unaltered behaviors, indicating that the currently established 5-day protocol of tamoxifen treatment (40 mg/kg bid) for inducible mutagenesis has no or little effects on the behavior of C57BL/6 male mice after a latency period of 4 weeks. These results are important for all studies using tamoxifen-induced mutagenesis since this protocol obviously does not evoke alterations in general behaviors such as locomotion, exploration or anxiety-like behaviors, which might confound more complex behavioral analyses, nor does it affect standard tests for learning and memory, such as Morris Water Maze, contextual and cued Fear Conditioning and T-Maze learning.

Dopamine receptor 3 (D3) knockout mice show regular emotional behaviour.

The "Dopamine Deficiency Hypothesis" and a considerable number of recent pharmacological studies propose to thoroughly verify and improve the standard of knowledge regarding a possible role of dopamine in the pathogenesis and treatment of depression. To elucidate the potential role of D3 receptors in the development of a depressive-like phenotype, we subjected D3 receptor knockout mice to a series of selected behavioural paradigms particularly focussing on depressive-like traits. In our experimental design we exposed animals with a deficiency of the D3 receptor (D3-/-) to a standardised behavioural test battery, in which general changes of locomotion, exploration, anxiety and depressive-like characteristics (i.e. Learned Helplessness, Sucrose Consumption and Forced Swim test) can be detected. Thorough behavioural phenotyping, however, neither revealed behavioural consequences on the basal level (locomotion, exploration) nor depressive- or anxiety-like alterations. Hence, these results do not indicate an evident involvement of the D3 receptor in the development of a depression-like syndrome in mice for now. This does, however, not exclude the D3 receptor as a potential target for pharmacotherapy.

Differential regulation of nerve growth factor and brain-derived neurotrophic factor in a mouse model of learned helplessness.

Stress-induced helplessness in rodents constitutes a well-defined model to investigate neurobiological mechanisms of depression. Neurotrophins like nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have both been shown to be involved in neurobiological changes of physiological and pathological reactions to stress. In this study we investigated NGF and BDNF protein levels in the frontal cortex and hippocampus in mice treated with an established model of inducible helplessness via electric footshocks compared to untreated controls at various times (0 h up to 14 days after treatment). NGF levels were transiently decreased by one forth in the frontal cortex of shocked mice at 6 h after the stress treatment, whereas BDNF levels remained unchanged in the brain areas investigated throughout the time course. In addition, frontal cortex BDNF levels showed a significantly higher concentration in the right compared to the left hemisphere (up to 3-fold). This effect was detectable independently of treatment, namely in shocked and control mice at any time point measured. In conclusion, a transient decrease of frontal NGF constitutes the most striking correlate of neurobiological changes in this animal model of stress-induced change of behaviour. Interhemispherical differences of BDNF content in the frontal cortex are a new finding that might reflect intracerebral side dominance. Thus, subsequent studies of frontal cortex BDNF expression should carefully consider an interhemispherical variance to avoid misinterpretation.

Adenocarcinoma in Crohn's colitis.

A case of Crohn's disease with carcinoma of the rectum is reported, bringing the number of reported cases to 44. Although the exact incidence of carcinoma arising in a segment of Crohn's disease is not known, a review of the literature emphasizes that there does seem to be a definite increased risk.