Biology subjects

Kaushik, R.

Publications and source records attributed to Kaushik, R..

23 records · Page 2Linked to original sources

bioRxiv2020

A molecular mechanism by which amyloid-β induces transcriptional inactivation of CREB in Alzheimer's Disease

Synaptic dysfunction caused by soluble {beta}-Amyloid (A{beta}) is a hallmark of the early stage of Alzheimers disease (AD) and is tightly linked to cognitive decline. A{beta} induces by yet unknown mechanisms disruption of transcriptional activity of cAMP- responsive element-binding protein (CREB), a master regulator of cell survival and plasticity-related gene expression. Here, we report that A{beta} elicits cytonuclear trafficking of Jacob, a protein serves as a mobile signaling hub that docks a signalosome to CREB, which induces transcriptional inactivation and subsequent synapse impairment and eventually loss in AD. The small chemical compound Nitarsone selectively hinders assembly of this signalosome and thereby restores CREB transcriptional activity. Nitarsone prevents impairment of synaptic plasticity as well as cognitive decline in mouse models of AD. Collectively, the data suggest that targeting Jacob induced CREB shutoff is a therapeutic avenue against early synaptic dysfunction in AD.

neuroscience↗

bioRxiv2019

LGI1 downregulation increases neuronal circuit excitability

LGI1 (Leucine-Rich Glioma-Inactivated 1) is a secreted trans-synaptic protein that interacts presynaptically with Kv1.1 potassium channels and ADAM23, and postsynaptically, influencing AMPA receptors through a direct link with the ADAM22 cell adhesion protein. Haploinsufficiency of LGI1 or autoantibodies directed against LGI1 are associated with human epilepsy, generating the hypothesis that a subacute reduction of LGI1 is sufficient to increase network excitability. We tested this hypothesis in ex vivo hippocampal slices and in neuronal cultures, by subacutely reducing LGI1 expression with shRNA. Injection of shRNA-LGI1 in the hippocampus increased dentate granule cell excitability and low frequency facilitation of mossy fibers to CA3 pyramidal cell neurotransmission. Application of the Kv1 family blocker, alpha-dendrotoxin, occluded this effect, implicating the involvement of Kv1.1. This subacute reduction of LGI1 was also sufficient to increase neuronal network activity in neuronal primary culture. These results indicate that a subacute reduction in LGI1 potentiates neuronal excitability and short-term synaptic plasticity, and increases neuronal network excitability, opening new avenues for the treatment of limbic encephalitis and temporal lobe epilepsies. Significant StatementDown-regulation of LGI1 protein increases excitability at mossy fiber to CA3 pyramidal cell synapses and in hippocampal primary cultures. These alterations alter network function and so could contribute to symptoms observed in patients affected by limbic encephalitis.

neuroscience↗

bioRxiv2019

Epigenetic mechanism of carbohydrate sulfotransferase 3 (CHST3) downregulation in the aging brain

Neural extracellular matrix (ECM) is a complex molecular meshwork surrounding neurons and glial cells in the extracellular space. Structural and functional state of ECM in the brain is tightly regulated by various components of neural ECM such as hyaluronic acid, chondroitin sulfate proteoglycans, link proteins, tenascins, various matrix-modifying enzymes such as chondroitin sulfate synthases and carbohydrate sulfotransferase together with matrix-degrading enzymes. Age-dependent accumulation of ECM molecules is implicated in the age-associated decline in synaptic and cognitive functions. Understanding age-associated changes in the expression of genes involved in regulating various components of ECM can provide an insight into the role of ECM in the aging brain. Hence, in this study, we compared the expression levels of ECM regulating genes in three groups of mice: 2-3 months old mice (2-3M), 22- to 26-month-old mice (22-26M) and more than 30-month-old mice (>30M). Using qPCR, we discovered that in the hippocampus of >30M old mice, the majority of ECM related genes are downregulated, while genes related to neuroinflammation are highly upregulated. This pattern was accompanied by a decrease in cognitive performance of the >30M old mice and was most correlated among ECM-related genes with the downregulation of carbohydrate sulfotransferase 3 (CHST3) gene expression. Interestingly, in 24-26M mice, no general decrease in the expression of ECM related genes was observed, although we still found the upregulation in neuroinflammatory genes and downregulation of CHST3. Further analysis of epigenetic mechanisms revealed a decrease in H3K4me3, three methyl groups at the lysine 4 on the histone H3 proteins, associated with the promoter region of CHST3 gene in non-neuronal (NeuN-negative) but not in neuronal (NeuN-positive) cells. We conclude that in 22-26 M old brains there are minor changes in expression of the studied bona fide neural ECM genes but there is a prominent epigenetic dysregulation of the CHST3 gene responsible for 6-sulfation of chondroitin sulfates, which may lead to impaired brain plasticity and cognitive decline.

neuroscience↗

bioRxiv2019

Dopamine modulates the integrity of the perisynaptic extracellular matrix at excitatory synapses

In the brain, Hebbian-type and homeostatic forms of plasticity are affected by neuromodulators like dopamine (DA). Modifications of the perisynaptic extracellular matrix (ECM), controlling functions and mobility of synaptic receptors as well as diffusion of transmitters and neuromodulators in the extracellular space, are crucial for the manifestation of plasticity. Mechanistic links between synaptic activation and ECM modifications are largely unknown. Here, we report that neuromodulation via D1-type DA receptors can induce targeted ECM proteolysis specifically at excitatory synapses of rat cortical neurons via proteases ADAMTS-4 and -5. We show that receptor activation induces increased proteolysis of brevican (BC) and aggrecan, two major constituents of the adult ECM, in vivo and in vitro. ADAMTS immunoreactivity is detected near synapses, and shRNA-mediated knockdown reduced BC cleavage. We outline a molecular scenario how synaptic activity and neuromodulation are linked to ECM rearrangements via increased cAMP levels, NMDA receptor activation, and intracellular calcium signaling.

neuroscience↗

bioRxiv2019

The impact of distillery effluent irrigation on plant-growth-promoting traits and taxonomic composition of bacterial communities in agricultural soil

Long-term irrigation of agricultural fields with distillery effluent (DE) may alter the physical, chemical and biological properties of the soil. Microorganisms are critical to the maintenance of soil health and productivity. However, the impact of DE irrigation on activity and taxonomy of soil microorganisms is poorly understood. Here we studied plant-growth-promoting (PGP) traits and taxonomic composition of bacterial communities in agricultural soil irrigated with DE in conjugation with irrigation water, using cultivation-dependent and - independent methods. Most of the bacterial isolates obtained from DE irrigated soil were found to display PGP traits (phosphate solubilization, siderophore, indolic compounds and ammonia production). Diverse bacterial taxa were found in both culturable bacterial community and 16S rRNA gene clone library, which belonged to bacterial phyla Proteobacteria (Alpha-, Beta- and Gamma- subdivisions), Firmicutes, Actinobacteria, Acidobacteria, Bacteroidetes and Gemmatimonadates. Overall, these results indicate that PGP traits and taxonomic diversity of soil bacterial communities were not severely impacted by DE irrigation.

microbiology↗