Chronic administration of atypical antipsychotics improves behavioral and synaptic defects of STOP null mice.

International audienceINTRODUCTION: Recent studies have suggested that schizophrenia is associated with alterations in the synaptic connectivity involving cytoskeletal proteins. The microtubule-associated protein stable tubule only polypeptide (STOP) plays a key role in neuronal architecture and synaptic plasticity, and it has been demonstrated that STOP gene deletion in mice leads to a phenotype mimicking aspects of positive and negative symptoms and cognitive deficits classically observed in schizophrenic patients. In STOP null mice, behavioral defects are associated with synaptic plasticity abnormalities including defects in long-term potentiation. In these mice, long-term administration of typical antipsychotics has been shown to partially alleviate behavioral defects but, as in humans, such a treatment was poorly active on deficits related to negative symptoms and cognitive impairments. Here, we assessed the effects of risperidone and clozapine, two atypical antipsychotics, on STOP null mice behavior and synaptic plasticity. RESULTS: Long-term administration of either drug results in alleviation of behavioral alterations mimicking some negative symptoms and partial amelioration of some cognitive defects in STOP null mice. Interestingly, clozapine treatment also improves synaptic plasticity of the STOP null animals by restoring long-term potentiation in the hippocampus. DISCUSSION: All together, the pharmacological reactivity of STOP null mice to antipsychotics evokes the pharmacological response of humans to such drugs. Totally, our study suggests that STOP null mice may provide a useful preclinical model to evaluate pharmacological properties of antipsychotic drugs

PLoS ONE

Although many clinical pathological states are now detectable using imaging and biochemical analyses, neuropsychological tests are often considered as valuable complementary approaches to confirm diagnosis, especially for disorders like Alzheimer's or Parkinson's disease, and schizophrenia. The touchscreen-based automated test battery, which was introduced two decades ago in humans to assess cognitive functions, has recently been successfully back-translated in monkeys and rodents. We focused on optimizing the protocol of three distinct behavioral paradigms in mice: two variants of the Paired Associates Learning (PAL) and the Visuo-Motor Conditional Learning (VMCL) tasks. Acquisition of these tasks was assessed in naive versus pre-trained mice. In naive mice, we managed to define testing conditions allowing significant improvements of learning performances over time in the three aforementioned tasks. In pre-trained mice, we observed differential acquisition rates after specific task combinations. Particularly, we identified that animals previously trained in the VMCL paradigm subsequently poorly learned the sPAL rule. Together with previous findings, these data confirm the feasibility of using such behavioral assays to evaluate the power of different models of cognitive dysfunction in mice. They also highlight the risk of interactions between tasks when rodents are run through a battery of different cognitive touchscreen paradigms

Potentiel translationnel d'une méthodologie basée sur des écrans tactiles pour évaluer les capacités cognitives chez la souris

This thesis work aimed to specify the potential of an innovative methodology latterly adapted in mice from neuropsychological tasks used in Humans. After the optimization of 3 assays (PAL, VMCL, PVD) taxing various cognitive functions in animals, different behavioral studies have gradually revealed: (1) the putative existence of proactive interferences over consecutive learnings in touchscreen tasks; (2) no acquisition deficit in Tg2576 mice (a transgenic model of Alzheimer’s Disease) in these paradigms, whatever the amyloid load considered; (3) the specific involvement of the dorsal striatum during the acquisition of VMCL and PAL tasks and the key role of the hippocampus during the recall of the latter task. As exemplified by the PAL task, our results suggest that despite momentous efforts in order to ensure the translational feature of touchscreen cognitive tasks, certain adaptations inherent to each species deeply influence the nature of underlying neurobiological substrates.Ce travail visait à évaluer le potentiel d’une méthodologie innovante récemment adaptée à la Souris sur la base de tests neuropsychologiques utilisés en clinique humaine. Après optimisation de 3 tâches (PAL, VMCL, PVD) ciblant différentes fonctions cognitives chez l’animal, nos études ont établi : (1) l’existence possible d’interférences proactives lors d’apprentissages consécutifs ; (2) l’absence de déficit d’acquisition chez les souris de la lignée Tg2576 (modèle transgénique de la maladie d’Alzheimer), quelle que soit l’étendue de la charge amyloïde ; (3) l’implication spécifique du striatum dorsal lors de l’acquisition des tâches de VMCL et PAL, et celle de l’hippocampe lors du rappel de cette dernière tâche. Ces derniers résultats suggèrent qu’en dépit des efforts déployés pour s’assurer du caractère translationnel d’une tâche cognitive dans le paradigme du touchscreen, certaines adaptations inhérentes à chaque espèce influencent profondément les bases neurobiologiques associées

Acquisition curves in naive mice trained either in the sPAL (similar objects) or the dPAL (different objects) tasks.

<p>* p<0.05 and **p<0.01 vs the dPAL group.</p

Acquisition curves in naive mice trained under various conditions in the VMCL task.

<p>*p<0.05 group 4 vs group 1 and p<0.01 group 4 vs group 3.</p

Global design of touchscreen experiments.

<p>In experiments A and B, naive mice were trained in the dPAL, sPAL or VMCL tasks according to specific learning conditions (groups 1–4, from top to bottom). In experiment C, most of the mice previously trained in a first touchscreen paradigm were assessed in a different task; because of their experience, early stages of pokey training were purposely skipped. For animals trained in stages with defined limited holding times (LHT), corresponding values are given in white. FD: Food Deprivation; IT: „Initial Touch“; MT: „Must Touch“; MI: „Must Initiate“; PI: „Punish Incorrect“; PT: „Pre-Training“.</p

Global repartition of the correct responses of all animals assessed in the PAL tasks (left panel) or in the VMCL task (right panel).

<p>In both PAL paradigms, there are six possible object-place combinations. In the VMCL task, mice can only respond to the left or the right part of the screen after the first central nose-poke.</p

Effect of a previous training experience in touchscreen boxes on the acquisition of a new task.

<p>Comparison of the acquisition curves of naive vs trained mice in the dPAL (left panel), the VMCL (central panel) or the sPAL task (right panel). *p<0.05 and ***p<0.001 vs the sPAL (task 1).</p

Additional parameters measured in touchscreen boxes during experiments A, B and C.

<p>CT: Correction Trials; CTL: Correct Touch Latency; ITL: Incorrect Touch Latency; ML: Magazine Latency.</p><p>All parameters are expressed as mean values ± SEM.</p><p>*p<0.05,</p><p>**p<0.01 <i>vs</i> sPAL group (task 1);</p>##<p>p<0.01 <i>vs</i> VMCL conditions 4 group.</p