Altered expression of histone and synaptic plasticity associated genes in the hippocampus of streptozotocin-induced diabetic mice

University of Newcastle, Callaghan, NSW, Australia.
Metabolic Brain Disease (Impact Factor: 2.4). 07/2013; 28(4). DOI: 10.1007/s11011-013-9418-y
Source: PubMed

ABSTRACT Accumulating evidence indicates that hyper-glycaemia is deleterious to brain function, in particular to the hippocampus. It is thought this hippocampal dysfunction may contribute to hyperglycaemia related cognitive impairment, such as that which manifests with diabetes. In the present study, we investigated the effects of diabetes-related hyperglycaemia on hippocampal gene expression, in order to identify potential mechanisms that might be associated with the cognitive dysfunction that develops with diabetes mellitus. Genome-wide gene expression profiling was carried out on the hippocampi from streptozotocin (STZ)-induced diabetic mice, and from vehicle treated control mice. Genes of interest that satisfied expression fold-change and statistical criteria, and that were considered to be potentially associated with cognitive function, were further tested by real time, quantitative polymerase chain reaction (qPCR) analysis. We found that STZ-induced diabetes resulted in decreased hippocampal expression of genes involved in epigenetic regulation and synaptic plasticity, for example, histone deacetylases and glycogen synthase kinase 3 beta (HDACs and GSK3β). We also found increased expression of genes involved in signalling cascades related to cell growth, cell survival and energy metabolism, such as neurotropic tyrosine kinase receptor type 2, apolipoprotein E, and protein tyrosine phosphatase receptor type (Ntrk2, APOE, PTPRT). To our knowledge this is the first study to demonstrate a gene expression profile implicating epigenetic modifications and alterations of synaptic plasticity associated genes in diabetes mellitus. The present study will improve our understanding of the neural mechanisms that might underpin diabetes-related cognitive dysfunction.

1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Working memory deficit is the core neurocognitive disorder in schizophrenia patients. To identify the factors underlying working memory deficit in schizophrenia patients and to explore the implication of possible genes in the working memory using genome-wide association study (GWAS) of schizophrenia, computerized delay-matching-to-sample (DMS) and whole genome genotyping data were obtained from 100 first-episode, treatment-naïve patients with schizophrenia and 140 healthy controls from the Mental Health Centre of the West China Hospital, Sichuan University. A composite score, delay-matching-to-sample total correct numbers (DMS-TC), was found to be significantly different between the patients and control. On associating quantitative DMS-TC with interactive variables of groups × genotype, one SNP (rs1411832), located downstream of YWHAZP5 in chromosome 10, was found to be associated with the working memory deficit in schizophrenia patients with lowest p-value (p = 2.02 × 10 −7). ConsensusPathDB identified that genes with SNPs for which p values below the threshold of 5 × 10 −5 were significantly enriched in GO:0007155 OPEN ACCESS Int. J. Mol. Sci. 2015, 16 2146 (cell adhesion, p < 0.001). This study indicates that working memory, as an endophenotype of schizophrenia, could improve the efficacy of GWAS in schizophrenia. However, further study is required to replicate the results from our study.
    International Journal of Molecular Sciences 01/2015; 16(1):2145-2161. DOI:10.3390/ijms16012145 · 2.46 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: IntroductionType 1 Diabetes (T1D) can have a significant impact on brain structure and function, which is referred to: ‘Type 1 diabetes-associated cognitive decline’ (T1DACD). Diabetes duration, early onset diseases and diabetes associated complications are all proposed as contributing factors for sustaining a T1DACD. However, no comparison between the differences in children and adults with T1D are made. To obtain more clarity into the occurrence and effects of a T1DACD in T1D, the purpose of this meta-analysis is to give an update and to study the differences in children and adults and to analyse the T1DACD contributing factors.Methods Two electronic databases were consulted: Pubmed and ISI Web of Knowledge. Literature until the end of 2012 was included. Effect sizes (Cohen's d), which are the standardized differences between the experimental and the control group, were calculated.ResultsSignificant findings of this study is a small to modest decrease in cognitive performance in T1D patients compared to non-diabetic controls. Children with T1D performed worse while testing for the executive function, full IQ and motor speed while T1D adults performed worse while testing the full/verbal and performance IQ, part of the executive function, memory, spatial memory and motor speed. Episodes of severe hypoglycaemia, chronic hyperglycaemia and age of onset can be significant influencing factors on the cognitive function in T1D.Conclusions This review adds that T1DACD is more severe in adults compared to children, suggesting that age and diabetes duration contribute to this T1DACD.
    Journal of Diabetes 07/2014; 6(6). DOI:10.1111/1753-0407.12193 · 2.35 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Previous work has shown a reduction of apical dendritic length and spine density in neurons from the CA1 hippocampus subfield of spontaneously hypertensive rats (SHR). These abnormalities are prevented by treatment for 2 weeks with 17 β -estradiol. In view of the fact that diabetes and hypertension are comorbid diseases, we have now studied the effect of Streptozotocin-induced diabetes on the dendritic tree and spines of CA1 hippocampus neurons, and also compared the regulation of these parameters by 17 β -estradiol in diabetic and normoglycemic SHR. Twenty week old male SHR received iv 40 mg/kg Streptozotocin or vehicle and studied one month afterwards. A group of normoglycemic and hyperglycemic SHR also received sc a single 17 β -estradiol pellet or vehicle for 2 weeks. Hippocampus sections were impregnated with silver nitrate following a modified Golgís method and the arbor of CA1 pyramidal neurons analyzed by the Sholĺs method. 17 β -estradiol treatment of normoglycemic SHR reversed the reduced length of apical dendrites, the low spine density and additionally decreased blood pressure. Diabetic SHR showed increased length of apical and basal dendrites but reduced spine density compared to normoglycemic SHR. Diabetes also decreased blood pressure of SHR. Treatment with 17 β -estradiol of diabetic SHR enhanced dendritic length, increased dendritic spine density and further decreased blood pressure. Thus, changes of cytoarchitecture of CA1 neurons due to 17 β -estradiol treatment of normoglycemic SHR persisted after diabetes induction. A decrease of blood pressure may also contribute to the central effects of 17 β -estradiol in SHR diabetic rats.
    Neuroscience 09/2014; 280. DOI:10.1016/j.neuroscience.2014.09.030 · 3.33 Impact Factor