Combining adverse factors to build a new 3-hit model of schizophrenia

Solenn Percelay (1) , Valentine Bouët (1) , Thomas Freret (1) , Michel Boulouard (1)

1 COMETE - Mobilités : Vieillissement, Pathologie, Santé

Schizophrenia is a disabling psychiatric disease found in approximately 1% of the population, with an unknown etiology. Most symptoms can be categorised into one of three types: positive symptoms (hallucinations, deliriums), negative symptoms (social withdrawal, anhedonia), and cognitive deficits such memory issues and altered executive functions. Currently patients are treated with antipsychotic drugs, which are only symptomatic and not curative. Unfortunately, these treatments do not cover the entirety of symptoms and are inefficient in 30 % of patients. Moreover, cognitive symptoms can even be worsened by antipsychotics. There is, therefore, a crucial need to find treatments that are more efficient. In this context, we are developing a mouse model of schizophrenia based on three factors (3-hit), which take into account the multifactorial nature of this pathology. The present study aims at investigating the respective effects of three factors, and their combination. The factors are the following: i. a partial genetic deletion of MAP6 gene (heterozygous mice), ii. an early-life stress triggered by maternal separation of 9-day old pups for 24 hours, and iii. a chronic administration of MK801 (0.05mg/kg, i.p., 5 days) in early adulthood. A behavioural exploration was performed to assess working memory (spontaneous alternation), long term memory (object recognition), sociability and social recognition (two steps of the approach avoidance test), anxiety-like behaviour and locomotor activity (open field). Then, density of parvalbumin-positive neurons in prefrontal cortex and hippocampus were measured via immunochemistry. Our first results showed that each factor, taken separately (1-hit), induced some behavioural deficits: MAP6 partial deletion impairs working memory; maternal separation impairs social recognition, and MK801 induces deficits in all tests. The 3-hit group showed an alteration of working memory and social recognition performances, and an increased distance travelled in open field, particularly during the first five minutes of test. Behavioural results are encouraging for the development of a new schizophrenia model. Construct validity is relevant and face validity is interesting given alteration of cognitive functions such as working memory. Ongoing immunochemistry study will give possible mechanisms involved.

Mots clés: Schizophrenia; Model; Mice; Behaviour

Domaines: Sciences cognitives; Neurobiologie; Pharmacologie

Solenn Percelay, Valentine Bouët, Thomas Freret, Michel Boulouard. Combining adverse factors to build a new 3-hit model of schizophrenia. XXIIème journées de l'Ecole Doctorale normande de Biologie Intégrétive, Santé, Environnement, Mar 2019, Caen, France. , 2019. ⟨hal-02135476⟩