Abstract
Both Disrupted-In-Schizophrenia-1 (DISC1) and dopamine receptors D2R have significant contributions to the pathogenesis of schizophrenia. Our previous study demonstrated that DISC1 binds to D2R and such protein-protein interaction is enhanced in patients with schizophrenia and Disc1-L100P mouse model of schizophrenia (Su et al., 2014). By uncoupling DISC1 × D2R interaction (trans-activator of transcription (TAT)-D2pep), the synthesized TAT-peptide elicited antipsychotic-like effects in pharmacological and genetic animal models, without motor side effects as tardive dyskinesia commonly seen with typical antipsychotic drugs (APDs), indicating that the potential of TAT-D2pep of becoming a new APD. Therefore, in the current study, we further explored the APD-associated capacities of TAT-D2pep. We found that TAT-D2pep corrected the disrupted latent inhibition (LI), as a hallmark of schizophrenia associated endophenotype, in Disc1-L100P mutant mice—a genetic model of schizophrenia, supporting further APD’ capacity of TAT-D2pep. Moreover, we found that TAT-D2pep elicited nootropic effects in C57BL/6NCrl inbred mice, suggesting that TAT-D2pep acts as a cognitive enhancer, a desirable feature of APDs of the new generation. Namely, TAT-D2pep improved working memory in T-maze, and cognitive flexibility assessed by the LI paradigm, in C57BL/6N mice. Next, we assessed the impact of TAT-D2pep on hippocampal long-term plasticity (LTP) under basal conditions and upon stimulation of D2 receptors using quinpirole. We found comparable effects of TAT-D2pep and its control TAT-D2pep-scrambled peptide (TAT-D2pep-sc) under basal conditions. However, under stimulation of D2R by quinpirole, LTP was enhanced in hippocampal slices incubated with TAT-D2pep, supporting the notion that TAT-D2pep acts in a dopamine-dependent manner and acts as synaptic enhancer. Overall, our experiments demonstrated implication of DISC1 × D2R protein-protein interactions into mechanisms of cognitive and synaptic plasticity, which help to further understand molecular-cellular mechanisms of APD of the next generation.
Highlights
Schizophrenia is a chronic brain disorder associated with severe psychotic symptoms which lead to disability
Efficacy of TAT-D2pep to Rescue the Disrupted Latent Inhibition in Disc1-L100P Mutant Mice Disc1-L100P mice express deficit of latent inhibition (LI), which was rescued by atypical antipsychotic drugs (APDs), clozapine and pharmacological compounds—glycogen synthase kinase-3 (GSK-3) and PDE4 inhibitors, as potentially new APDs (Clapcote et al, 2007; Lipina et al, 2011a)
We found that TAT-D2pep facilitated synaptic plasticity upon D2R stimulation, which may contribute to its action as APD with nootropic capacity
Summary
Schizophrenia is a chronic brain disorder associated with severe psychotic symptoms which lead to disability. The prevalence of schizophrenia remains stably high and currently near 21 million people suffer from this mental disorder, according to World Health Organization (World Health Statistics, 2017). There are no effective treatments of cognitive impairments in schizophrenics as typical and atypical antipsychotic drugs (APDs) only partly ameliorate the positive or negative symptoms of schizophrenia (Meltzer, 1995) and near 60% of schizophrenics are resistant to APDs treatment (Meltzer and Kostacoglu, 2001). D2 dopamine receptor (D2R) is a classical target of current APDs and most effective APDs antagonize the D2R (Seeman and Kapur, 2000; Glatt et al, 2003). There is a need for a deeper understanding of the D2R signaling pathways in order to reveal new therapeutic targets for more effective APDs with reduced side effects
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