Intrinsic metabolic and immune impairments in a genetic mouse model of schizophrenia
Martina Belmonte1, Sofia Lopez Cardoso1, Anabella A Di Pietro2
1Instituto de Biología y Medicina Experimental (IBYME), Vuelta de Obligado 2490, Ciudad de Buenos Aires, (CABA), Argentina.
Abstract:
Schizophrenia is a disorder of still unknown aetiology characterized by positive, negative and cognitive symptoms. The first evident signs emerge at the end of adolescence and the beginning of adulthood as a psychotic episode. Patients are then treated with antipsychotics to ameliorate positive symptoms. However, this pharmacological approach is ineffective for negative and cognitive ones. Schizophrenia patients also exhibit metabolic and immune alterations, regardless of antipsychotic treatment. Clinical research in this field is challenging, as there is no way to identify people at risk before the first psychotic episode, and once it emerges, antipsychotic treatment is applied, worsening metabolic and immune profiles which may be detrimental for cognitive and negative symptoms. A faithful animal model of schizophrenia may be valuable to understand molecular events and brain regions involved in each of the symptoms, evaluate novel pharmacological compounds for unattended symptoms and explore objective diagnostic strategies. Here, we show that the selective dopamine D2 receptor deletion from parvalbumin interneurons, a mutation that results in schizophrenia-like phenotypes, causes intrinsic metabolic and immune defects in mice, in a similar way to what is described in schizophrenia patients. Mutant animals show dysglycaemia and dyslipidaemia, abnormal white blood cell counts, increased neutrophil-to-lymphocyte ratio, CD4/CD8 ratio imbalances, increased circulating C-reactive protein levels and reactive microglia. Therefore, selective dopamine D2 receptor deletion causes a wide spectrum of phenotypes resembling those described in patients. This animal line may be a useful research tool to expand our knowledge on the aetiology of schizophrenia.
Insights
Researchers developed a mouse model for schizophrenia by deleting dopamine D2 receptors in specific neurons. This model exhibits metabolic and immune changes similar to patients, offering new research avenues for schizophrenia treatment.
Area of Science:
- Neuroscience and Psychiatry
- Genetics and Molecular Biology
- Immunology and Metabolism
Background:
- Schizophrenia's etiology remains unknown, presenting positive, negative, and cognitive symptoms.
- Current antipsychotics primarily treat positive symptoms, leaving negative and cognitive deficits unaddressed.
- Schizophrenia patients exhibit metabolic and immune alterations independent of antipsychotic treatment.
Purpose of the Study:
- To develop a faithful animal model for schizophrenia research.
- To investigate molecular events and brain regions implicated in schizophrenia symptoms.
- To explore novel pharmacological compounds and diagnostic strategies for schizophrenia.
Main Methods:
- Generated a mouse model with selective dopamine D2 receptor deletion from parvalbumin interneurons.
- Phenotypically characterized mutant mice for schizophrenia-like symptoms, including metabolic and immune profiles.
- Assessed metabolic parameters (dysglycaemia, dyslipidaemia) and immune markers (blood cell counts, C-reactive protein, microglia activation).
Main Results:
- The dopamine D2 receptor deletion induced schizophrenia-like phenotypes in mice.
- Mutant mice displayed intrinsic metabolic defects, including dysglycaemia and dyslipidaemia.
- Significant immune alterations were observed, such as abnormal white blood cell counts, increased neutrophil-to-lymphocyte ratio, CD4/CD8 imbalances, elevated C-reactive protein, and reactive microglia.
Conclusions:
- Selective dopamine D2 receptor deletion from parvalbumin interneurons creates a comprehensive schizophrenia-like animal model.
- This model recapitulates key metabolic and immune dysregulations seen in schizophrenia patients.
- This novel animal line serves as a valuable tool for advancing schizophrenia research, particularly for unattended symptoms and diagnostic strategies.
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