Modelling depression in animals and the potential antidepressant effect of histaminergic modulation

Depression is at the top position for "years lived with disability" (Smith, 2014). Its aetiology is unknown, but the pathogenesis implicates changes in glutamatergic neuronal plasticity. Glutamatergic plasticity likely mediates the effects of antidepressants acting through monoamines. Histamine is a monoaminergic neuromodulator able to regulate glutamatergic plasticity and synaptic transmission. The Flinders sensitive line (FSL) rat has face and predictive validity as model of depression when using traditional behavioural tests. However, these tests are usually missing complex explorative strategies that the animal performs in novel situations and that may be a relevant feature for a model of depression. We aimed to profile the FSL rat in terms of explorative strategies and coping styles displayed in a novel environment. The multivariate concentric square field™ (MCSF) consists of zones with different degrees of aversion. In the MCSF test, FSL rats showed lower exploratory drive, less recurrence to the shelter, and more risk assessment compared to Sprague Dawley rats, but no difference in risk-taking behaviours. In the novel cage test (consisting in a new bare environment) and in the home cage change test (to measure social behaviours), the FSL rat displayed a reactive coping style, described by immobility and lower aggression compared to Sprague Dawley rats. This profile shows similarities with temperaments and coping styles related to depression. Depression is linked to alteration of glutamatergic plasticity and similar alterations have been found in the hippocampus of FSL rats. Histamine H3 receptor (H3R) antagonists have displayed antidepressant properties in preclinical studies. We assessed the antidepressant properties of the H3R antagonist, clobenpropit, and its effect on hippocampal glutamatergic transmission in FSL rats. In the forced swim test, both systemic and hippocampal injections of clobenpropit reduced the immobility time. Clobenpropit improved memory in the novel object recognition and passive avoidance tests, with no effect on anxiety-related tests. Clobenpropit applied on hippocampal slices enhanced long-term synaptic potentiation (LTP), and, accordingly, in vivo administration increased the hippocampal levels of the NMDA receptor subunit GluN2A. Clobenpropit's effects both in the forced swim test and on LTP were prevented by blocking the hippocampal H1 and H2 receptors. In summary, clobenpropit exhibits antidepressant properties and regulates hippocampal glutamatergic plasticity, likely by an increase of histamine release and subsequent activation of the H1 and H2 receptors. Histamine receptors trigger intracellular signalling involved in the regulation of glutamatergic synaptic receptors, a mechanism that can affect synaptic strength. We assessed the histaminergic modulation of glutamatergic synaptic strength by recording miniature excitatory postsynaptic currents (mEPSCs) from CA1 pyramidal neurons in hippocampal slices from Sprague Dawley rats. The H1R, but not the H2R, agonist reduced mEPSC frequency, with no change of amplitude, suggesting a reduction of vesicle release probability. However, the paired-pulse facilitation (a measure of presynaptic release probability) was not altered by either the H1R or the H2R agonist, possibly due to a differential modulation of evoked versus spontaneous vesicle release. However, a postsynaptic origin of mEPSC frequency reduction cannot be excluded

Neurotrophic-mimetic strategy to rescue synaptic plasticity and cognitive functions in a mouse model of Down syndrome

Down syndrome (DS) or trisomy 21 is the most frequent genetic cause of intellectual disability in children and adults. Although numerous studies have shown that cognitive impairment possibly arises from dysfunction of the hippocampal circuit, there has been little progress in defining effective treatments. Previous studies have shown that impaired synaptic plasticity of mature hippocampal neurons and decreased hippocampal adult neurogenesis are main determinants in reducing cognitive functions in DS animal models. Currently, most preclinical therapeutic approaches in DS mice have focused on rescuing either one or the other of these impairments. Here, we have found that the expression of Brain-Derived Neurotrophic Factor (BDNF) is decreased in the brains of individuals with DS. Interestingly, a large body of literature indicates that BDNF signaling modulates both synaptic plasticity, and adult neurogenesis. Therefore, we propose here to promote BDNF/TrkB signaling using a BDNF-mimetic drug with the twofold aim of rescuing synaptic plasticity and increase adult neurogenesis toward the rescue of cognitive functions in the Ts65Dn mouse model of DS. Our results indicate that indeed promoting BDNF/TrkB signaling rescued hippocampal synaptic plasticity, increased hippocampal adult neurogenesis and restored cognitive performances in different behavioral tasks in Ts65Dn mice. The molecular mechanisms of impaired BDNF/TrkB signaling in trisomic mice are currently under investigation. Overall, our experiments show in a reliable animal model of DS the efficacy of a novel and multifaceted therapeutic approach with good potential to be translated into clinical practice

Altered explorative strategies and reactive coping style in the FSL rat model of depression

Modeling depression in animals is based on the observation of behaviors interpreted as analogue to human symptoms. Typical tests used in experimental depression research are designed to evoke an either-or outcome. It is known that explorative and coping strategies are relevant for depression, however these aspects are generally not considered in animal behavioral testing. Here we investigate the Flinders Sensitive Line (FSL), a rat model of depression, compared to the Sprague-Dawley (SD) rat in three independent tests where the animals are allowed to express a more extensive behavioral repertoire. The multivariate concentric square field T (MCSF) and the novel cage tests evoke exploratory behaviors in a novel environment and the home cage change test evokes social behaviors in the re-establishment of a social hierarchy. In the MCSF test, FSL rats exhibited less exploratory drive and more risk-assessment behavior compared to SD rats. When re-exposed to the arena, FSL, but not SD rats, increased their exploratory behavior compared to the first trial and displayed risk-assessment behavior to the same extent as SD rats. Thus, the behavior of FSL rats was more similar to that of SDs when the rats were familiar with the arena. In the novel cage test FSL rats exhibited a reactive coping style, consistent with the reduced exploration observed in the MCSF. Reactive coping is associated with less aggressive behavior. Accordingly, FSL rats displayed less aggressive behavior in the home cage change test. Taken together, our data show that FSL rats express altered explorative behavior and reactive coping style. Reduced interest is a core symptom of depression, and individuals with a reactive coping style are more vulnerable to the disease. Our results support the use of FSL rats as an animal model of depression and increase our understanding of the FSL rat beyond the behavioral dimensions targeted by the traditional depression-related tests

Altered explorative strategies and reactive coping style in the FSL rat model of depression

Modeling depression in animals is based on the observation of behaviors interpreted as analogue to human symptoms. Typical tests used in experimental depression research are designed to evoke an either-or outcome. It is known that explorative and coping strategies are relevant for depression, however these aspects are generally not considered in animal behavioral testing. Here we investigate the Flinders Sensitive Line (FSL), a rat model of depression, compared to the Sprague-Dawley (SD) rat in three independent tests where the animals are allowed to express a more extensive behavioral repertoire. The multivariate concentric square field T (MCSF) and the novel cage tests evoke exploratory behaviors in a novel environment and the home cage change test evokes social behaviors in the re-establishment of a social hierarchy. In the MCSF test, FSL rats exhibited less exploratory drive and more risk-assessment behavior compared to SD rats. When re-exposed to the arena, FSL, but not SD rats, increased their exploratory behavior compared to the first trial and displayed risk-assessment behavior to the same extent as SD rats. Thus, the behavior of FSL rats was more similar to that of SDs when the rats were familiar with the arena. In the novel cage test FSL rats exhibited a reactive coping style, consistent with the reduced exploration observed in the MCSF. Reactive coping is associated with less aggressive behavior. Accordingly, FSL rats displayed less aggressive behavior in the home cage change test. Taken together, our data show that FSL rats express altered explorative behavior and reactive coping style. Reduced interest is a core symptom of depression, and individuals with a reactive coping style are more vulnerable to the disease. Our results support the use of FSL rats as an animal model of depression and increase our understanding of the FSL rat beyond the behavioral dimensions targeted by the traditional depression-related tests

Neurotrophic-mimetic strategy to rescue synaptic plasticity and cognitive functions in a mouse model of Down syndrome

Down syndrome (DS) is caused by the triplication of human chromosome 21, and it is the most frequent genetic cause of cognitive disabilities. Although numerous studies have shown that cognitive impairment possibly arises from dysfunction of the hippocampal circuit, there is little insight into neurobiological bases of these abnormalities, and thus, there has been little progress in defining effective treatments. The trisomic Ts65Dn mouse model of DS reproduces the essential cognitive disabilities of the human syndrome. Previous studies in this model have shown that impaired synaptic plasticity of mature hippocampal neurons and decreased hippocampal adult neurogenesis are main determinants in reducing cognitive functions in DS animal models. Currently, most preclinical therapeutic approaches in the DS mouse models have focused on rescuing either one or the other of these impairments. Interestingly, we have found that the expression of Brain-Derived Neurotrophic Factor (BDNF) is decreased in the brains of DS patients. On the other hand, BDNF signaling modulates both synaptic plasticity, and adult neurogenesis. Therefore, we propose to promote BDNF/TrkB signaling using a BDNF-mimetic drug with the twofold aim of rescuing synaptic plasticity and increase adult neurogenesis toward the rescue of cognitive functions in Ts65Dn mice. Our results indicate that indeed promoting BDNF/TrkB signaling rescued hippocampal synaptic plasticity, increased dentate adult neurogenesis and restored cognitive performances in different behavioral tasks in Ts65Dn mice. Overall, our experiments show in a reliable animal model of DS the efficacy of a novel and multifaceted therapeutic approach with good potential to be translated into clinical practice

Dysfunction of homeostatic control of dopamine by astrocytes in the developing prefrontal cortex leads to cognitive impairments.

Astrocytes orchestrate neural development by powerfully coordinating synapse formation and function and, as such, may be critically involved in the pathogenesis of neurodevelopmental abnormalities and cognitive deficits commonly observed in psychiatric disorders. Here, we report the identification of a subset of cortical astrocytes that are competent for regulating dopamine (DA) homeostasis during postnatal development of the prefrontal cortex (PFC), allowing for optimal DA-mediated maturation of excitatory circuits. Such control of DA homeostasis occurs through the coordinated activity of astroglial vesicular monoamine transporter 2 (VMAT2) together with organic cation transporter 3 and monoamine oxidase type B, two key proteins for DA uptake and metabolism. Conditional deletion of VMAT2 in astrocytes postnatally produces loss of PFC DA homeostasis, leading to defective synaptic transmission and plasticity as well as impaired executive functions. Our findings show a novel role for PFC astrocytes in the DA modulation of cognitive performances with relevance to psychiatric disorders