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

Abstract

Introduction: 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.

Fig. 1

Social investigation test. Number (a and b) and total duration (c and d) of contacts with the intruder in placebo and long-term risperidone (a and c) or clozapine (b and d) -treated WT and STOP-null mice. STOP-null mice treated with placebo present a social withdrawal when compared with their WT littermates [ns, *, **: p>0.05, p<0.05, p<0.01, respectively, KO vs WT placebo]. Chronic treatment with risperidone or clozapine significantly improved social behaviour in STOP-null mice [#, ##: p<0.05, p<0.01, respectively, between KO groups, with A different from C, p<0.01for risperidone (a and c) and p<0.05 for clozapine (b and d) long-term treatments]. Note that clozapine and risperidone are not administrated the same way (injection and drinking water, respectively) preventing direct comparisons between the two groups

Fig. 2

Marble burying test. Number of buried marbles in placebo and long-term risperidone (a) or clozapine (b) -treated WT and STOP-null mice. STOP-null mice treated with placebo bury fewer marbles when compared with their WT littermates [*: p<0.05, KO vs WT placebo]. Chronic treatment of STOP-null mice with risperidone or clozapine enhanced the number of buried marbles in a non significant [ns] way

Fig. 3

Forced swim test. Total time of immobility in placebo and long-term risperidone (a) or clozapine (b) -treated WT and STOP-null mice. Immobility time was longer in STOP-null mice treated with placebo compared with their WT littermates [ns, *: p>0.05, p<0.05, respectively, KO vs WT placebo]. Administration of a chronic treatment with either risperidone or clozapine produced a significant decrease in immobility time in STOP-null mice [#, ##: p<0.05, p<0.01, respectively, between KO groups, with A different from C, p<0.01 for risperidone (a) and p<0.05 for clozapine (b) long-term treatments]

Fig. 4

Spontaneous alternation task (Y-Maze) in placebo and long-term risperidone-treated WT and STOP-null mice. STOP-null mice treated with placebo present an impairment of spatial working memory when compared to their WT littermates [*: p<0.05, KO vs WT placebo]. Chronic treatment with risperidone slightly improved STOP-null mice performance in the Y maze although not significantly [ns]

Fig. 5

Electrophysiological recordings of LTP. (a) Normalized field EPSP amplitude recorded during 10 min before and 60 min after tetanus (100 Hz, 1 sec) for placebo (n = 10 slices), clozapine 3 mg/kg/day (n = 16 slices) and clozapine 10mg/kg/day (n = 6 slices) STOP null mice. (b) Normalized field EPSP amplitudes between 30 and 40 min after tetanus. In wild type mice, LTP values were similar in all studied groups (untreated, placebo and clozapine-treated) and the value for WT placebo group is shown for comparisons; STOP-null mice treated with placebo present an impairment of LTP when compared to their WT littermates [**: p<0.01, KO vs WT placebo]. Only the dose of 10 mg/kg/day of clozapine significantly improved LTP of chronically-treated mice [#: p<0.05 between KO groups, with A different from C, p<0.05]