Mechanism Of Learning And Memory In Spinocerebellar Ataxia Type 3 Mice

Background: Spinocerebellar ataxia(SCA)is an inherited neurodegenerative disorder.Prevalence rate of about 8-12/10 million,mostly between 30-40 years of age,the survival period of about 10-20 years.At present,there are more than 30 kinds of SCA subtypes.In China,the proportion of SCA3 subtype is the highest,accounting for SCA of 40%-48%.SCA with progressive cerebellar ataxia,dysarthria and ataxia were the main clinical manifestations,sometimes accompanied by ophthalmoplegia,pyramidal sign,cognitive dysfunction,peripheral neuropathy and retinal pigment degeneration etc..Patients with SCA have been found to have cognitive dysfunction,and the incidence,severity and type of cognitive impairment of different subtypes of SCA are different.The most basic reason for the onset of SCA3 may be the cellular toxicity of polyglutamine(poly Q)extended mutant ataxin-3.Heat shock protein 70(Hsp70)is also associated with the formation of intranuclear inclusion bodies in the nucleus,Hsp70 promotes the degradation of mutant ataxin3 protein and thus reduces the cytotoxicity.Arginine vasopressin(AVP),is mainly synthesized and secreted in the hypothalamic paraventricular nucleus and supraoptic nucleus,involved in the process of learning and memory of the peptide,enhance the memory effect.In the cerebellum,thalamus,medulla oblongata,cortex,striatum,hippocampus and spinal cord of animals and humans,the AVP receptors were measured in the brainstem,hippocampus and amygdala.There are a series of executive,visual spatial,linguistic and emotional disorders in “Cerebellar cognitive affective syndrome”.Signals of higher motor and cognitive and emotional functions were introduced into the cerebellum through the basal ganglia,the pontine nucleus and the cerebellar peduncle,The signal is transmitted through the dentate nucleus and the ventrolateral nucleus of the thalamus,“Cerebellar thalamic cortical ring”.Therefore,the contents of AVP in cerebellum,hypothalamus,cerebral cortex,hippocampus,pituitary,spinal cord and plasma were measured.Discuss the relationship between AVP and learning and memory.Because of the prevalence rate of SCA is low,with complicated clinical manifestations,between different races,the same race between different subtypes,the same subtype between different families,and even the same subtype with a different clinical manifestations are not the same,which make it difficult for the clinical study of cognitive impairment.At present,there is no research on spatial learning and memory of SCA3 patients.At the same time,there is no report on the spatial learning and memory and Ataxin-3 inclusion bodies,AVP content in SCA3 patients.Objective: To evaluate the spatial learning and memory function of SCA3 model mice,and to explore the relationship between the formation of intranuclear inclusion bodies with ataxin-3 protein and the content of AVP.To study whether Hsp70 and AVP can be used as a target for learning and memory impairment in SCA3.Methods: Male SCA3 mice and male wild type(WT)mice of 12 months(body weight was 20-23g)were from Animal Center of Zhengzhou University,Zhengzhou,Henan,China.The male SCA3 mice were identified by the polymerase chain reaction(PCR).SCA3 mice were used as experimental group,and the rest were WT mice.Spatial reference learning and memory were evaluated in a Morris water maze.The content of ataxin-3 and Hsp70 were examined by immunohistochemistry.AVP concentration was measured by radioimmunoassay.Results: 1 the spatial learning and memory ability of SCA3 mice was decreased compared with that of WT mice.2.The distance traveled and latency to the platform,not swimming velocity of the SCA3 mice over the training sessions in the Morris water maze tests were reduced compared to the WT mice.3.the Ataxin-3 protein was found in the cerebellum and hippocampus of the SCA3 mice,and the inclusion bodies were formed in the nucleus of the Hsp70 mice.4.The SCA3 mice had a decrease of AVP concentration in the cerebral cortex,hypothalamus,hippocampus and cerebellum,not in the spinal cord,pituitary and serum compared to the WT mice.Conclusion: The spatial learning and memory dysfunction in SCA3 mice may be related to the formation of intranuclear inclusions and the AVP content in the cerebral cortex,hypothalamus,hippocampus and cerebellum of the hippocampus and cerebellum of ataxin-3 protein.Background: The clinical manifestations of spinocerebellar ataxia(SCA)are complex.More and more evidences indicate that SCA patients have cognitive impairment,including spatial learning and memory decline.There is no effective treatment,currently only to alleviate symptoms or slow disease progression.We tried to confirm and search for the mechanism of cognitive impairment in patients with SCA by different angles and methods.Many clinical studies have found,The incidence of dementia in SCA3 patients was 5%~13%.Some SCA3 patients with cognitive impairment.Depression and apathy are common in patients with SCA3.However,changes in the progression of depression and apathy to cognitive impairment and dementia have not been reported in relation to age and disease progression.The median age of the mice was 10-15 months,For the elderly group,the mice should be at least 18 months old.SCA3 patients in the incidence of 30-40 years old,So we take the December age mice as the research object,At the same time,we studied the relationship between the development of learning and memory and the content of AVP with the age and disease progression in SCA3 mice aged 3 months、6 months and 18 months.SCA patients with cerebellar gray matter,cerebellar white matter,globus pallidus,hippocampus,ventral diencephalon,thalamus,putamen etc.have obvious atrophy.In the blood,central nervous system,cerebrospinal fluid,there are AVP.In this study,we investigated whether the decline in learning and memory function in SCA patients was related to the concentration of AVP in the relevant sites,and the change of the correlation with age.SCA3 is the most common subtype of SCA,so this paper takes SCA3 mice as the research object.The relationship between spatial learning and memory and AVP levels in patients with SCA3,and the relationship between AVP concentration and learning and memory in SCA3 mice of different ages has not been reported.Objective: To compare the relationship between the changes of learning and memory and the changes of arginine vasopressin in SCA3 mice of different age groups.Methods: Male SCA3 mice and male wild type(WT)mice(body weight was 20-23g)were from Animal Center of Zhengzhou University,Zhengzhou,Henan,China.The age of the mice were 3 months,6 months,12 months and 18 months.The male SCA3 mice were identified by the polymerase chain reaction(PCR).SCA3 mice were used as experimental group,and the rest were WT mice.AVP concentration was measured by radioimmunoassay.Results: 1.The distance traveled and latency to the platform of the SCA3 mice significantly prolonged,which compared with those of the WT mice,in the Morris water maze tests for the 12 and 18 months groups.There was no significant difference between the 3 and 6 months groups.There was no significant difference in swimming speed of each group.2.AVP concentration in the cerebral cortex,hypothalamus,hippocampus and cerebellum were decreased significantly compared with those of the WT mice,for the age of 12 and 18 months groups.The concentration did not differ between SCA3 mice and WT mice.There was no significant change of AVP concentration in the spinal cord,pituitary and serum.Conclusion: The spatial learning and memory dysfunction in SCA3 mice aged 18 months and 12 months may be related to the AVP content in the cerebral cortex and hippocampus.Background: Spinocerebellar ataxia(SCA)is a hereditary disease of the nervous system,and there is a large body of evidence that SCA patients have cognitive impairment,including spatial learning and memory decline.Myelin basic protein(MBP)is the major myelin protein in the central nervous system,which plays an important role in the promotion of axonal regeneration.Hippocampus plays a role in memory and spatial orientation.We may be able to change the MBP content in the hippocampus in the treatment of SCA patients with memory disorders.H2 S is a gaseous signal molecule,which has the function of resisting neurotoxicity,regulating neuroendocrine,protecting mitochondria,and ensuring the normal functioning of the nervous system.H2 S can improve the selectivity of Nmethyl-D-aspartate(NMDA)receptor regulates the nervous system reaction,improve the hippocampal long-term potentiation(LTP),on learning and memory has an important regulatory function.Previous studies have shown that mitochondrial dysfunction exists in patients with SCA.Mitochondria are the sites of ATP synthesis by aerobic oxidation of cells,which directly affect the ability of ATP synthesis.The reduction of ATP formation can also cause cell edema,endoplasmic reticulum expansion,and even cell degeneration and necrosis.The content of MBP in the myelin sheath depends on the normal energy supply of the mitochondria,while the H2 S has the function of protecting mitochondria.At present,there is no report on the correlation between the changes of MBP content in the myelinated nerve fiber pathway and the content of H2 S in the hippocampus of SCA3 mice.It is suggested that the function of mitochondria can be improved by changing the content of hydrogen sulfide in hippocampus,To change the content of MBP in the myelinated nerve fibers in the hippocampus to reduce the damage of myelin sheath.Memory impairment in SCA3 mice may be improved.Objective: To study the H2S、MBP of hippocampus in spinocerebellar ataxia type 3 mice and to explore the effect of sodium borohydride on the hippocampus.Methods: Male SCA3 mice(body weight was 20-23g)were from Animal Center of Zhengzhou University,Zhengzhou,Henan,China.The male SCA3 mice were identified by the polymerase chain reaction(PCR).1.Intraperitoneal injection of different concentrations of Na HS solution.The body weight and H2 S content were measured.2.Spatial reference learning and memory were evaluated in a Morris water maze.3.Determination of H2 S in hippocampus by methylthionine chloride spectrophotometry.Immunohistochemical method was used to detect the expression of MBP in hippocampal CA1 region.1.The results of Morris water maze showed that the spatial learning and memory ability of SCA3 mice of 12 months groups were lower than that of WT mice.2.Hydrogen sulfide content in hippocampus of SCA3 mice of 12 months groups decreased significantly than that of WT mice.3.The results of immunohistochemistry showed that the content of MBP in the hippocampus of the SCA3 mice of 12 months groups was significantly lower than that in the WT mice.Results:Conclusion: It is suggested that the function of mitochondria can be improved by changing the content of hydrogen sulfide in hippocampus,To change the content of MBP in the myelinated nerve fibers in the hippocampus.Memory impairment in SCA3 mice may be improved.