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Learned Helplessness Regulates Synapse Related LncRNAs in Mouse Hippocampus

ABSTRACT: Purpose: RNA sequencing (RNA-Seq) has revolutionized systems-based analysis of cellular pathways. The goal of this study is to find learned helplessness/depression regulates synapse related long noncoding RNAs (lncRNAs) in mouse hippocampus Methods: compared the differential expression of mRNA and lncRNAs in learned helplessness (LH) group, nonlearned helplessness (NLH) group and Ctrl group, using GO analysis, pathway enrichment and co-expression Results: We found that 2163 or 1396 mRNA are different expressed in LH compared with Control or NLH group, 199 or 142 lncRNAs are different expressed in LH compared with Control or NLH group, respectivly. Then we applied complex bioinfomatics analysis to do lncRNAs functional analysis, finding dendritic spine morphogenesis, chemical synaptic transmission and synaptic potential signaling pathway are common between LH group compared with Ctrl group and LH group compared with NLH group. Further more we found that the identified lncRNAs are mediating several cellular functions such as: protein transport, ion transport, mRNA processing, regulation of dendritic spine development, regulation of neuron projection development and regulation of GTPase activity. Interestingly, there was strong regulation of lncRNAs related to synapse. Conclusions: Our study is the first attempt to explore the possibility that lncRNAs might be involved in helplessness using RNA sequencing. And we found some lncRNAs have strong functions in synapse regulation.

ORGANISM(S): Mus musculus

PROVIDER: GSE102965 | GEO | 2017/08/24

SECONDARY ACCESSION(S): PRJNA399643

REPOSITORIES: GEO

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Project description:Many forms of synaptic plasticity are critically dependent upon production of cGMP to trigger activity-dependent increases in synaptic size and strength. Phosphodiesterase 9A (PDE9A) is a high affinity, cGMP-specific phosphodiesterase with widespread distribution in the central nervous system. Inhibition of PDE9A results in significant accumulation of cGMP in brain tissue and cerebrospinal fluid (CSF) of rodents, and increases CSF cGMP in human volunteers. We hypothesized that chronic exposure to a PDE9A inhibitor, and the associated elevations in brain cGMP could provide a therapeutic benefit to vulnerable synapses chronically exposed to Aβ in transgenic mice over-expressing human mutant amyloid precursor protein (Tg2576 mice). A total of N=20 animals per group of 4 month old Tg2576 mice and non-transgenic littermates (WT) were implanted with Alzet osmotic minipumps to deliver vehicle or the PDE9A inhibitor PF-04447943. Neurobehavioral outcomes were measured as conditioned fear response after 28 days of treatment and subsequently brains were harvested for measurement of Aβ, gene expression profiling or synaptic density as assessed by Golgi staining of dendrites. Dendritic spine density on apical dendrites of CA1 neurons exhibited a small but significant deficit in the density of dendritic spines in vehicle treated Tg2576 mice as compared to WT mice. This deficit was ameliorated by 30 days of exposure to PF-04447943. No significant drug effect was observed in WT mice. No significant effects of drug treatment were observed on Aβ levels in Tg2576 mice. Behavioral analysis of Tg2576 mice showed deficits in fear conditioning as early as 2 months old, and therefore were considered unlikely to be due to the accumulation of oligomeric Aβ. These deficits were not affected by drug treatment. Transcriptional profiles of Tg2576 mice treated with drug compared to vehicle showed evidence of regulation of pathways related to synaptic plasticity and remodeling of the dendritic cytoskeleton, consistent with stabilization of vulnerable spine structure. These data supports the hypothesis that PDE9A inhibition can stabilize vulnerable synapses early in the Alzheimer’s disease process. 4-month old Tg2576 mice and non-transgenic (WT) littermates were implanted with minipumps to deliver vehicle or the PDE9A-inhibitor, PF-04447943, for 28 days. At the end of the study, hippocampus and frontal cortex were dissected from n=8 mice per group, RNA was isolated, and hybridized to Affymetrix 430 2.0 mouse whole genome microarray.

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Learned Helplessness Regulates Synapse Related LncRNAs in Mouse Hippocampus

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