OXYS rats with hereditary hyperproduction of active oxidative radicals and early disorders in the mitochondrial structure and functions are an interesting model for studies of age-specific features of synaptic plasticity. The formation of long-term posttetanic potentiation in the mossy fibers-CA3 pyramidal neuron system were studied in hippocampal slices from Wistar and OXYS rats aged 3 and 4.5 months (young), 11 (middle-aged), and 18 months (old). No appreciable age-related differences were detected in the amplitudes and latencies of stimulatory postsynaptic summary potentials of the mossy synapses evoked by test stimuli in Wistar and OXYS rat groups of different age and between the two strains. The capacity to induction and formation of long-term posttetanic potentiation and its value decreased in 18-month-old Wistar rats, which attested to disorders in synaptic plasticity of old animals. The capacity to induction and formation of long-term posttetanic potentiation and its value in OXYS were lower than Wistar rats of the same age in all the studied groups.

Copy number variations (CNVs) of the human CNTN6 gene caused by megabase-scale microdeletions or microduplications in the 3p26.3 region are often the cause of neurodevelopmental disorders, including intellectual disability and developmental delay. Surprisingly, patients with different copy numbers of this gene display notable overlapping of neuropsychiatric symptoms. The complexity of the study of human neuropathologies is associated with the inaccessibility of brain material. This problem can be overcome through the use of reprogramming technologies that permit the generation of induced pluripotent stem (iPS) cells from fibroblasts and their subsequent in vitro differentiation into neurons. We obtained a set of iPS cell lines derived from a patient carrier of the CNTN6 gene duplication and from two healthy donors. All iPS cell lines displayed the characteristics of pluripotent cells. Some iPS cell lines derived from the patient and from healthy donors were differentiated in vitro by exogenous expression of the Ngn2 transcription factor or by spontaneous neural differentiation of iPS cells through the neural rosette stage. The obtained neurons showed the characteristics of mature neurons as judged by the presence of neuronal markers and by their electrophysiological characteristics. Analysis of allele-specific expression of the CNTN6 gene in these neuronal cells by droplet digital PCR demonstrated that the level of expression of the duplicated allele was significantly reduced compared to that of the wild-type allele. Importantly, according to the sequencing data, both copies of the CNTN6 gene, which were approximately 1 Mb in size, showed no any additional structural rearrangements.

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.

Parameters of long-term potentiation in the system mossy fibers-CA3 pyramidal neurons in hippocampal slices in experimental animals vary during the formation of chronic opiate dependence. During the first day of morphine treatment, the value of potentiation was significantly lower than in controls. Starting from day 8 and at early stages of dependence (days 25-29), facilitation of long-term potentiation was recorded. Incubation of the slices with L-type Ca(2+)-channel blocker nifedipine did not change the response to the test stimuli and did not affect potentiation induction in hippocampal slices from control and morphine-treated animals. Nifedipine had no effect on long-term potentiation of mossy fibers in the control and at early terms of morphine treatment, but significantly reduced its facilitation at later terms.