Uncoupling DISC1 × D2R Protein-Protein Interactions Facilitates Latent Inhibition in Disc1-L100P Animal Model of Schizophrenia and Enhances Synaptic Plasticity via D2 Receptors

Tatiana V Lipina; Nikolay A Beregovoy; Alina A Tkachenko; Ekaterina S Petrova; Marina V Starostina; Qiang Zhou; Shupeng Li

doi:10.3389/fnsyn.2018.00031

Uncoupling DISC1 × D2R Protein-Protein Interactions Facilitates Latent Inhibition in Disc1-L100P Animal Model of Schizophrenia and Enhances Synaptic Plasticity via D2 Receptors

Front Synaptic Neurosci. 2018 Sep 7:10:31. doi: 10.3389/fnsyn.2018.00031. eCollection 2018.

Authors

Tatiana V Lipina^{1

2}, Nikolay A Beregovoy³, Alina A Tkachenko^{1

2}, Ekaterina S Petrova^{1

2}, Marina V Starostina³, Qiang Zhou⁴, Shupeng Li⁴

Affiliations

¹ Federal State Budgetary Scientific Institution, Scientific Research Institute of Physiology and Basic Medicine, Novosibirsk, Russia.
² Institute for the Medicine and Psychology of Novosibirsk State University, Novosibirsk, Russia.
³ Institute of Molecular Biology and Biophysics, FRC FTM, Novosibirsk, Russia.
⁴ School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, China.

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.

Keywords: D2R; DISC1; Disc1-L100P mouse model of schizophrenia; latent inhibition; synaptic plasticity.