Periodic Reporting for period 1 - Schizo-EPICOG (Inflammatory processes underlying cognitive deficits in schizophrenia: epigenetic mechanisms and pharmacological regulation)
Periodo di rendicontazione: 2018-04-11 al 2020-04-10
Schizophrenia is a chronic and severe psychiatric disorder that affects more than 20 million people worldwide. Despite its relatively low prevalence, the burden of schizophrenia is increasing globally and is ranked among the top 20 most disabling disorders.
Cognitive deficits represent nuclear symptoms of schizophrenia and are considered prognostic factors of the disease. Moreover, they are resistant to the currently available treatments and it is clinically suspected that atypical antipsychotics might worsen cognitive conditions of schizophrenic patients. Previous data indicate the involvement of epigenetic regulation of histone deacetylases (HDACs) in this effect and the possibility of neuroinflammmatory activity as the inductor mechanism (Ibi et al, Nat Neurosci. 2017. 20:1247-1259). Despite more than a century of studying schizophrenia, its cause remains unknown. In the etiopathogenesis of schizophrenia a double-hit phenomenon has been suggested. Thus, a prenatal priming event that would induce vulnerability is followed by a second stressful hit in peripuberty. Physio- and psychopathology could emerge from these mechanisms through neuroinflammatory hyperactivity.
The general aim of the present project was to study the relationship between cognitive deficits and neuroinflammatory activity. To do so, a traslational "double hit" mouse model (in male and female animals) based on the maternal inmmune activation during gestation followed by social isolation at puberty has been developed and validated. In this animal model, we have assessed: i) the cognitive, social and psychotic status; ii) the gene and protein expression of inflammatory signalling proteins and HDACs; and iii) the modulation of behaviural responses by chronic treatment with the antipsychotic clozapine, the inflammatory activity inhibitor minocycline or the combination of both. Moreover, histone acetylation status in postmortem human prefrontal cortex of subjects with schizophrenia under antipsychotic treatment or drug-free conditions and matched controls has been studied. In these subjects the possibility of an excess of inflammatory activity associated to epigenetic modifications and/or to the presence of antipsychotic treatment will be analyzed.
We have developed an original animal model resembling some behavioral and molecular alterations observed in schizophrenia, which might be a useful tool to understand the biological substrates underlying cognitive symptoms of the disease. Thus, new proposals for the development of novel therapeutic approaches would emerge from the project outcomes, especially to treat the “orphan symptoms” of schizophrenia such as cognitive deficits, which would have a major impact on patients’ quality of life. Moreover, this project, developed in a context of translational research in mental health, will contribute to a better understanding of the etiopathogenic basis of schizophrenia.
Cognitive deficits represent nuclear symptoms of schizophrenia and are considered prognostic factors of the disease. Moreover, they are resistant to the currently available treatments and it is clinically suspected that atypical antipsychotics might worsen cognitive conditions of schizophrenic patients. Previous data indicate the involvement of epigenetic regulation of histone deacetylases (HDACs) in this effect and the possibility of neuroinflammmatory activity as the inductor mechanism (Ibi et al, Nat Neurosci. 2017. 20:1247-1259). Despite more than a century of studying schizophrenia, its cause remains unknown. In the etiopathogenesis of schizophrenia a double-hit phenomenon has been suggested. Thus, a prenatal priming event that would induce vulnerability is followed by a second stressful hit in peripuberty. Physio- and psychopathology could emerge from these mechanisms through neuroinflammatory hyperactivity.
The general aim of the present project was to study the relationship between cognitive deficits and neuroinflammatory activity. To do so, a traslational "double hit" mouse model (in male and female animals) based on the maternal inmmune activation during gestation followed by social isolation at puberty has been developed and validated. In this animal model, we have assessed: i) the cognitive, social and psychotic status; ii) the gene and protein expression of inflammatory signalling proteins and HDACs; and iii) the modulation of behaviural responses by chronic treatment with the antipsychotic clozapine, the inflammatory activity inhibitor minocycline or the combination of both. Moreover, histone acetylation status in postmortem human prefrontal cortex of subjects with schizophrenia under antipsychotic treatment or drug-free conditions and matched controls has been studied. In these subjects the possibility of an excess of inflammatory activity associated to epigenetic modifications and/or to the presence of antipsychotic treatment will be analyzed.
We have developed an original animal model resembling some behavioral and molecular alterations observed in schizophrenia, which might be a useful tool to understand the biological substrates underlying cognitive symptoms of the disease. Thus, new proposals for the development of novel therapeutic approaches would emerge from the project outcomes, especially to treat the “orphan symptoms” of schizophrenia such as cognitive deficits, which would have a major impact on patients’ quality of life. Moreover, this project, developed in a context of translational research in mental health, will contribute to a better understanding of the etiopathogenic basis of schizophrenia.
One major aim of the present study was to create a translational “double-hit” animal model of schizophrenia in male and female mice, based in maternal immune activation (MIA, hit-1) —injection of poly (I: C) to pregnant dams, 7.5 mg / kg ip — and social isolation (SI, hit-2) in the peri-pubertal period (3–11 weeks). In the four experimental groups (hit-1, hit-2, double-hit and control) several behavioral paradigms related to the different symptom dimensions of schizophrenia (positive, negative and cognitive symptoms) have been conducted. Thus, we have assessed spontaneous locomotion (positive) and anxiety related behavior (negative) in the Open Field Test (OFT), hyperlocomotion induced by acute administration of amphetamine (positive), head-twitch response induced by acute administration of the hallucinogen DOI ( positive), sociability (negative), spontaneous alternation in the Y maze (cognitive) and novel object recognition test (cognitive).
These results have shown behavioral alterations in both single-hit and double-hit animal models in different symptomatic dimensions. In social and cognitive dimentions, a greater alteration is observed in the double-hit than in the single-hit models. This finding suggests that the present double-hit model may be useful in the evaluation of new drugs to treat the negative and cognitive symptomatology of the disease. Moreover, both males and female mice presented the behavioral alterations, indicating that this model is valid for both sexes.
At the molecular level, the gene and protein expression of the neuroinflammatory signaling proteins NF-κB and IκBα have been evaluated in the brain cortex of the animal models. Additionaly, the gene expression of different HDACs has also been evaluated. The obtained results showed alterations in the gene expression of some of these targets. These results prompted us to assess a pharmacological treatment based on the administration of minocycline (a tetracycline antibiotic with antiinflammatory properties) alone or in combination with the atypical antipsychotic clozapine. In the last stage of the present project we are analyzing the effects of those treatments in the different experimental groups of the double-hit animal model, both in males and females.
The results obtained to date derived from the Schizo-EPICOG project have been disseminated in 3 international conferences, 2 national workshops, in forums of the CIBERSAM (Center for Biomedical Research Network of Mental Health), in Researh social-networks (Research-gate) and also has been communicated to the general public in organized actions such as the European Researcher`s Night 2020 (https://www.ikertzaileengaua-ehu.org/rincon-europeo/(si apre in una nuova finestra)).
These results have shown behavioral alterations in both single-hit and double-hit animal models in different symptomatic dimensions. In social and cognitive dimentions, a greater alteration is observed in the double-hit than in the single-hit models. This finding suggests that the present double-hit model may be useful in the evaluation of new drugs to treat the negative and cognitive symptomatology of the disease. Moreover, both males and female mice presented the behavioral alterations, indicating that this model is valid for both sexes.
At the molecular level, the gene and protein expression of the neuroinflammatory signaling proteins NF-κB and IκBα have been evaluated in the brain cortex of the animal models. Additionaly, the gene expression of different HDACs has also been evaluated. The obtained results showed alterations in the gene expression of some of these targets. These results prompted us to assess a pharmacological treatment based on the administration of minocycline (a tetracycline antibiotic with antiinflammatory properties) alone or in combination with the atypical antipsychotic clozapine. In the last stage of the present project we are analyzing the effects of those treatments in the different experimental groups of the double-hit animal model, both in males and females.
The results obtained to date derived from the Schizo-EPICOG project have been disseminated in 3 international conferences, 2 national workshops, in forums of the CIBERSAM (Center for Biomedical Research Network of Mental Health), in Researh social-networks (Research-gate) and also has been communicated to the general public in organized actions such as the European Researcher`s Night 2020 (https://www.ikertzaileengaua-ehu.org/rincon-europeo/(si apre in una nuova finestra)).
The results from the Schizo-EPICOG project contribute to shed light into the molecular bases underlying the cognitive and social deficits associated to schizophrenia. These core symptoms of the disease are compleatly treatment-orphan and there is an urgent need for development of pro‐cognitive therapies. Thus, the present preclinical data regarding potential targets/drugs that could improve cogntion in schizophrenia patients is very relevant in the advance of the pharmacological treatment of the disease.
It is also relevant to point out the gender dimension taken into account within this research project. To develop the animal model of schizophrenia, female and male mice have been used, and we have shown that our model is valid for both sexes. Moreover, comparative analyses between males and females regarding behavioural and molecular outcomes have been studied. This approach has allowed us to assess whether there are significant differences attending to sex or not in behavioural and molecular alterations. Animal studies on schizophrenia including both males and females are scarce and there is little knowledge regarding gender gaps in the alterations observed in different animal models of the disease. Including both genders in the experimental design of this project has been challenging and has added a big effort; however, we strongly believe that it is of especial relevance working within a framework of translational research.
It is also relevant to point out the gender dimension taken into account within this research project. To develop the animal model of schizophrenia, female and male mice have been used, and we have shown that our model is valid for both sexes. Moreover, comparative analyses between males and females regarding behavioural and molecular outcomes have been studied. This approach has allowed us to assess whether there are significant differences attending to sex or not in behavioural and molecular alterations. Animal studies on schizophrenia including both males and females are scarce and there is little knowledge regarding gender gaps in the alterations observed in different animal models of the disease. Including both genders in the experimental design of this project has been challenging and has added a big effort; however, we strongly believe that it is of especial relevance working within a framework of translational research.