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.
