Spelling suggestions: "subject:"synaptic function"" "subject:"ynaptic function""
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The Role of LMO4 in the Regulation of Hippocampal and Amygdalar Synaptic FunctionQin, Zhaohong January 2013 (has links)
Synaptic activity can encode and store information in the brain through changes in synaptic strength as well as by control of gene expression. One corollary challenge becomes identifying these activity-dependent regulatory proteins and the underlying mechanisms associated with neuronal functions. By using biochemical, electrophysiological and behavioral approaches in combination with genetic and pharmacological manipulation, I report that LIM domain only 4 (LMO4) is a key regulator of calcium induced calcium release (CICR) and protein tyrosine phosphatase 1B (PTP1B) in the hippocampus and amygdala, respectively. Neuronal ablation of LMO4 in the glutamatergic neurons (LMO4KO) was associated with reduced promoter activity, mRNA, and protein expression of ryanodine receptor 2 (RyR2), suggesting the involvement of LMO4 in the transcriptional regulation. CICR function in LMO4KO mice was severely compromised, reflected by inefficient CICR-mediated electrophysiological responses including afterhyperpolarization, calcium rise from internal stores and glutamate release probability. These changes were accompanied with impaired hippocampal long term potentiation (LTP) and hippocampal-dependent spatial learning ability. LMO4 was also shown to exert a cytoplasmic regulation as an endogenous inhibitor for PTP1B that accounts for tyrosine dephosphorylation of mGluR5 in the amygdala. LMO4KO mice had elevated PTP1B activity and decreased mGluR endocannabinoid signaling, resulting in a profound anxiety phenotype. The potential clinical value of PTP1B/LMO4 is promising, given that intra-amygdala injection of the PTP1B inhibitor Trodusquemine or a PTP1B shRNA alleviated anxiety by restoring eCB signal in LMO4KO mice. Thus this study identified PTP1B as a potential therapeutic target for anxiety, besides the previous findings of its association with obesity and diabetes. Moreover, this PTP1B-mediated anxiety may be a general mechanism during chronic stress. Collectively, these findings identify that LMO4 plays an essential role for non-genomic and genomic regulation in central neurons, providing a mechanism for LMO4 to modulate a wide range of neuronal functions and behavior.
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Identification of novel apolipoprotein E receptor 2 splice variants and their role in synaptic transmissionOmuro, Kerilyn C. 03 February 2022 (has links)
Apolipoprotein E (APOE) is one of the most important genetic risk factors for late-onset sporadic Alzheimer’s disease (LOAD). APOE is a 35 kDa glycoprotein and ligand known to bind to members of the low-density lipoprotein receptor (LDLR) family, including APOE receptor 2 (apoER2; official gene name LRP8). ApoER2 is a type I transmembrane protein with a large extracellular domain (ECD) and a short cytoplasmic tail that can be proteolytic cleaved. In addition, apoER2 is enriched in the brain and plays an important role in synaptic function and plasticity. Interestingly, the ECD of apoER2 contains several ligand binding repeats that are organized into exons with aligning phase junctions, which allows exon skipping during alternative splicing to retain protein fidelity. The amount of alternative spliced isoforms distinguishes apoER2 from the rest of the LDLR family members. In fact, mouse Apoer2 has been identified as one of the top ten neuronal genes related to cell-type exon skipping events. Regarding human APOER2, we have identified over 40 different APOER2 isoforms from human brain using gene-specific primers and amplifying the N- and C-terminal open reading frame of APOER2. The majority of APOER2 variants consist of a diverse array of exon skipping events within the ligand binding domain (LBD). We therefore, hypothesized that human APOER2 splice variants act as functionally divergent isoforms that can influence ligand binding properties, receptor proteolysis and changes to synaptic function.
ApoER2 undergoes sequential proteolytic cleavage in response to ligand binding, resulting in the release of C-terminal fragments (CTFs) and transcriptionally active intracellular domain (ICD). We therefore, systematically tested whether the diversity of human N-terminal APOER2 splice variants lacking various LBDs affects APOER2 cleavage and signaling events. We found that alternative splicing of certain APOER2 exons generated different amounts of CTFs compared to full-length APOER2 (APOER2-FL). The pattern was not simply based on the number of ligand binding domains suggesting that excision of certain exons may alter the tertiary structure of the receptor sufficiently to make the receptor more or less accessible to cleavage and generation of CTFs. To further characterize APOER2 splice variants, we specifically examined APOER2 splice variants that generated the highest and lowest amounts of CTF generation compared to APOER2-FL and focused on APOER2 splice variant lacking exons 5-8 (Δ5-8) and lacking exons 4-6 (Δ4-6), respectively. The differential CTF generation of APOER2 Δ5-8 and Δ4-6 reflects the proteolytic release of the APOER2-ICD. This APOER2-ICD mediates transcriptional activation, facilitated by the Mint1 adaptor protein.
To investigate whether human N-terminal APOER2 splice variants influence APOE binding and receptor cleavage properties, we used microscale thermophoresis and tested the well-validated human APOE mimetic peptide. We found that specific exons or ligand-binding cassettes differentially affect APOE peptide binding to APOER2 splice variants. In addition, APOE peptide induces generation of APOER2-CTF acutely within one hour. Functionally, we demonstrated that APOER2 is required for spontaneous neurotransmitter release in mature neurons. Loss of mouse Apoer2 robustly decreased miniature event frequency in excitatory synapses compared to heterozygous Apoer2 neurons. We found APOER2-FL fully restored the miniature event frequency in excitatory synapses but not APOER2 Δ5-8. APOER2 Δ4-6 restored the miniature event frequency similar to heterozygous Apoer2 neurons. These results suggest that different human N-terminal APOER2 splice variants have distinct and differential synaptic properties signifying a role of APOER2 splice variants as regulators of synaptic function.
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GABA<sub>A</sub> Receptor Homeostasis at the <i>C. elegans</i> Neuromuscular JunctionSujkowski, Alyson L. 09 September 2010 (has links)
No description available.
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The polyunsaturated fatty acids, EPA and DPA exert a protective effect in the hippocampus of the aged ratKelly, L.E., Grehan, B., Chiesa, A.D., O'Mara, S.M., Downer, E., Sahyoun, George, Massey, Karen A., Nicolaou, Anna, Lynch, M.A. January 2010 (has links)
No / Age is characterized by deficits in synaptic function identified by decreased performance of aged animals in spatial learning tasks and reduced ability of animals to sustain long-term potentiation (LTP). Several cellular and molecular events are correlated with these deficits, many of which are indicative of cell stress. Thus there is evidence of age-related neuroinflammatory stress and oxidative stress and these have been linked with microglial activation which is likely to be primarily responsible for the age-related increase in production of proinflammatory cytokines and reactive oxygen species. It is significant that agents which decrease microglial activation are commonly associated with restoration of function. We set out to examine whether the n-3 polyunsaturated fatty acid docosapentaenoic acid (DPA), which is a metabolite of eicosapentaenoic acid (EPA), could modulate the age-related increase in microglial activation and the associated increase in oxidative changes and therefore impact on synaptic function in aged rats. We demonstrate that DPA possesses neurorestorative effects and is capable of downregulating microglial activation. The data show that it also decreases the coupled activation of sphingomyelinase and caspase 3, probably as a result of its ability to decrease age-related oxidative changes, and consequently attenuates the age-related decrease in spatial learning and LTP.
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A novel human tau knock‑in mouse model reveals interaction of Abeta and human tau under progressing cerebral amyloidosis in 5xFAD miceBarendrecht, Susan, Schreurs, An, Geissler, Stefanie, Sabanov, Victor, Ilse, Victoria, Rieckmann, Vera, Eichentopf, Rico, Künemund, Anja, Hietel, Benjamin, Wussow, Sebastian, Hoffmann, Katrin, Körber‑Ferl, Kerstin, Pandey, Ravi, Carter, Gregory W., Demuth, Hans‑Ulrich, Holzer, Max, Roßner, Steffen, Schilling, Stephan, Preuss, Christoph, Balschun, Detlef, Cynis, Holger 03 September 2024 (has links)
Background Hyperphosphorylation and intraneuronal aggregation of the microtubule-associated protein tau is a
major pathological hallmark of Alzheimer’s disease (AD) brain. Of special interest is the effect of cerebral amyloid beta
deposition, the second main hallmark of AD, on human tau pathology. Therefore, studying the influence of cerebral
amyloidosis on human tau in a novel human tau knock-in (htau-KI) mouse model could help to reveal new details on
their interplay.
Methods We studied the effects of a novel human htau-KI under fast-progressing amyloidosis in 5xFAD mice in
terms of correlation of gene expression data with human brain regions, development of Alzheimer’s-like pathology,
synaptic transmission, and behavior.
Results The main findings are an interaction of human beta-amyloid and human tau in crossbred 5xFADxhtau-KI
observed at transcriptional level and corroborated by electrophysiology and histopathology. The comparison of
gene expression data of the 5xFADxhtau-KI mouse model to 5xFAD, control mice and to human AD patients revealed
conspicuous changes in pathways related to mitochondria biology, extracellular matrix, and immune function.
These changes were accompanied by plaque-associated MC1-positive pathological tau that required the htau-KI
background. LTP deficits were noted in 5xFAD and htau-KI mice in contrast to signs of rescue in 5xFADxhtau-KI mice.
Increased frequencies of miniature EPSCs and miniature IPSCs indicated an upregulated presynaptic function in
5xFADxhtau-KI.
Conclusion In summary, the multiple interactions observed between knocked-in human tau and the 5xFAD-driven
progressing amyloidosis have important implications for future model development in AD.
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The Role of the HECT-Type Ubiquitin Ligases WWP1 and WWP2 in Nerve Cell Development and Function / Die Rolle der HECT-Typ Ubiquitin Ligasen WWP1 und WWP2 bei der Entwicklung und der Funktion von NervenzellenKishimoto-Suga, Mika 15 April 2011 (has links)
No description available.
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