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

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Submitted on 21 May 2019

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

Solenn Percelay, Valentine Bouët, Thomas Freret, Michel Boulouard

To cite this version:

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�

Combining adverse factors to build

a new 3-hit model of schizophrenia

Solenn Percelay, Valentine Bouet, Thomas Freret, Michel Boulouard

Contact : solenn.percelay@unicaen.fr

Introduction

Our first results showed that each factor, taken separately (1-hit), induced behavioral impairments: MAP6 partial deletion impairs working memory; maternal separation impairs social recognition, and MK801 induces deficits in all tests. The 3-hit group showed an increase of locomotor activity (positive-like symptoms), alteration of working memory and of social recognition performances.

These behavioral results are encouraging for the development of a new schizophrenia model. Indeed, construct validity is relevant, taken into account the multifactorial nature of this pathology. Face validity is interesting, notably given alteration of cognitive functions. Ongoing immunochemistry study will give possible mechanisms involved.

Ellenbroek et al. (2003). Behavioural pharmacology. Lewis, D. A. et al. (2012). Trends in neurosciences. Millan et al. (2016). Nature reviews Drug discovery. Shimizu et al. (2006). Schizophrenia research.

Working memory

Spontaneous alternation

Activity and anxiety

Open Field

Schizophrenia is a disabling psychiatric disease found in approximately 1% of the population, with an unknown etiology. 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 (Millan et al., 2016). Moreover, antipsychotics treatments can even worsen cognitive symptoms. 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 (Ellenbroek et

al., 2003). A behavioral exploration was performed, then, density of parvalbumin-positive neurons was measured via

immunohistochemistry (Lewis et al., 2012).

C57Bl6 MAP6 partial deletion (Microtubule Associated Protein, deficient in schizophrenia, Shimizu et al., 2006) Maternal separation P9 _P60-65

3-hit

Control

1-hit_MAP6

_{1-hit_MS}

1-hit_MK801

Results

Long term memory

Object recognition 1h Acquisition B A A A Retention

Sociability & social recognition

Approach avoidance test

0 25 50 75 100 Alternation % * * ~

Discussion and conclusion

Anova *: p<0,05

T test with comparison to reference value *: p<0,05; ~:0,05<p<0,1

0 5000 10000 15000 20000 Distance moved (cm) * * -50 -25 0 25 50 Sociability index * -50 -25 0 25 50 75

Social recognition index

* N=8 N=9 N=14 _N=9 N=8 -1.0 -0.5 0.0 0.5 1.0

Novel object recognition index

* * * *

Exclusion criteria: exploration time <20s

N=4 N=7

N=8 N=4