Disc1 Knockdown Induced Recognition Memory Deficits Associated With Disrupting Neural Oscillation Patterns In Mice

In recent years,schizophrenia and other mental diseases have caused great trouble to people’s life.Researchers have a deeper understanding of the genetic system structure of mental diseases.Some major mental disorders and genes are associated with chromosomal abnormalities.In order to make a breakthrough in the development of drugs for the treatment of mental diseases,we need to have a comprehensive understanding of the pathology,genetic basis and the changes of the oscillation of the brain neural network.The pathological mechanism of schizophrenia is very complex,involving a large number of gene interactions.Among them,(Disrupted in schizophrenia gene 1)gene is one of the most susceptible genes associated with mental illness.Many studies have shown that the gene is closely related to mental diseases,but there are few studies on the changes of neural oscillations.At present,there are few studies on the relationship between the knockdown of Disc1 gene and cognitive impairment from the perspective of neural oscillation.The phenomenon of neural concussion plays a key role in the nervous system in a dynamic form,which is closely related to the advanced cognitive activities such as information processing and memory consolidation.Our studies hypothesized that knockdown of affects genes associated with neurotransmitter receptors and disturbs neural oscillations,social and cognitive performance.In the sh RNA-group,we found that the mice with gene knockdown showed not only the impairments of social and cognitive abilities,but also abnormal neural oscillations.The results of bioinformatics analysis show that that the expression of GABAergic neurons and glutamate neuron neurotransmitter receptors related genes in hippocampus of mice was significantly reduced.The balance between excitatory and inhibitory neurons was broken.Our research shows that the impact of knockdown of gene on cognition is mainly due to concussion injury,which may be related to the obstruction of neurotransmitter transmission.Methods:Before the experiment,the mice were first adapted to the new environment suchas the feeding room,which was called the adaptation period.At the end of the adaptation period,the mice were randomly divided into two groups: sh RNA-Cont group(SHNC,n=8): C57 BL / 6J mice were injected with NC control virus in DG area of hippocampus;sh RNA-Disc1 group(sh Disc1,n=8): C57 BL / 6J mice were injected with AAV in DG area of hippocampus to interfere with the expression of Disc1.The adenovirus containing interference sequence was injected into the hippocampus of mice to construct the sh RNA-Disc1 group.After the mice recovered for 15 days,the position of signal acquisition was determined by stereo positioning instrument,and then the signal of neural oscillation was collected by electrophysiological instrument.A series of indicators such as the power distribution of the oscillation rhythm,Phase locking value,Evolution map approach,Phase-amplitude coupling modulation index was calculated by analysis algorithm,and compares the differences between the sh RNA-Cont group and the sh RNA-Disc1 group.We specifically compared the expression of genes related to nervous system development and synaptic plasticity between the sh RNA-Cont group and the sh RNA-Disc1 group,and used enrichment analysis and other means to explore the specific functions of the differentially expressed genes.Results:(1)The behavioral experiments of new and different objects and new and different positions showed that the cognitive and memory abilities of sh RNA-Disc1 mice were damaged.(2)In sh RNA-Disc1 group,the synchronization of the local field potential neural oscillation rhythm decreased,the transmission and flow intensity of the same specific rhythm information flow between the two brain regions decreased,and the coupling intensity between the low-frequency rhythm and the high-frequency amplitude decreased significantly.(3)Western blot was used to detect the expression level of DISC1 protein in the hippocampus of mice.Compared with the sh RNA-Cont group,the expression level of DISC1 protein in the hippocampus of the model group was significantly reduced.The results of bioinformatics enrichment analysis were consistent with the changes oflocal field potential oscillation in DG area of hippocampus in sh RNA-Disc1 group.Disc1 gene mainly affects the neural oscillation by affecting the neurotransmitter transmission of glutamate signaling pathway,cholinergic signaling pathway and GABAergic signaling pathway.Conclusion:In conclusion,the knockdown of Disc1 gene significantly affected the hippocampal oscillation pattern.After the knockdown of Disc1 gene,a large number of genes involved in synaptic plasticity,neurotransmitter transport and synaptic transmission changed and destroyed the balance between excitatory neuron pathway and inhibitory neuron pathway,which led to the abnormality of hippocampal neural oscillation mode in mice.Meanwhile,the experimental results of behavioral tests showed that the recognition memory ability of mice was damaged.The findings of this study may reveal the underlying mechanism of Disc1 induced mental disorders.