Biology subjects

Shetty, M. S.

Publications and source records attributed to Shetty, M. S..

5 recordsLinked to original sources

bioRxiv2025

Genetic inactivation of the Translin/Trax RNase activity alters small RNAs including miRNAs, disrupts gene expression and impairs distinct forms of hippocampal synaptic plasticity and memory

Neurons utilize RNA interference in the reversible translational repression of synaptically localized mRNAs, enabling rapid translation in response to synaptic activity. Two evolutionarily conserved proteins, Translin and Trax, form an RNase complex which processes miRNAs, tRNAs and siRNAs. To determine the specific role of the RNase activity of this complex in brain function, we employed a mouse line harboring a point mutation in Trax (E126A) that renders the Translin/Trax RNase inactive. At the molecular level, we found alterations in the levels of multiple small RNAs including miRNAs, tsRNAs and substantial downregulation of gene expression at the mRNA level in the hippocampus of TraxE126A mice. At the synaptic level, TraxE126A mice exhibit deficits in specific forms of long-term hippocampal synaptic plasticity. At the behavioral level, TraxE126A mice display impaired long-term spatial memory and altered open-field and acoustic-startle behavior. These studies reveal the functional role of Translin/Trax RNase in the mammalian brain.

neuroscience↗

bioRxiv2022

Chemogenetic enhancement of cAMP signaling renders hippocampal synaptic plasticity resilient to the impact of acute sleep deprivation

Sleep facilitates memory storage and even brief periods of sleep loss lead to impairments in memory, particularly memories that are hippocampus dependent. In previous studies, we have shown that the deficit in memory seen after sleep loss is accompanied by deficits in synaptic plasticity. Our previous work has also found that sleep deprivation is associated with reduced levels of cyclic adenosine monophosphate (cAMP) in the hippocampus, and that the reduction of cAMP mediates the diminished memory performance. Based on these findings, we hypothesized that cAMP acts as a mediator for not only the cognitive deficits caused by sleep deprivation, but also the observed deficits in synaptic plasticity. In this study, we expressed the heterologous Drosophila melanogaster Gs-protein coupled octopamine receptor (DmOct{beta}1R) in mouse hippocampal neurons. This receptor is selectively activated by the systemically injected ligand (octopamine), thus allowing us to increase cAMP levels in hippocampal neurons during a five-hour sleep deprivation period. Our results show that chemogenetic enhancement of cAMP during the period of sleep deprivation prevents deficits in a persistent form of long-term potentiation (LTP) that is induced at the Schaffer collateral synapses in the hippocampal CA1 region. We also found that elevating cAMP levels only in the early or later half of sleep deprivation successfully prevented LTP deficits. These findings reveal that cAMP-dependent signaling pathways are key mediators of sleep deprivation at the synaptic level. Targeting these pathways could be useful in designing strategies to prevent the impact of sleep loss. Significance statementInsufficient sleep is an issue with significant health and socioeconomic implications. This includes a negative impact on memory consolidation. Previous studies in mice found that acute sleep deprivation leads to deficits in hippocampal synaptic plasticity and memory, which are associated with reduced levels of the signaling molecule cAMP. In this study, we used a chemogenetic strategy to enhance cAMP levels in specific hippocampal neurons during sleep deprivation. We found that this made synaptic plasticity resilient to the negative effects of sleep deprivation. These findings reveal that cAMP-dependent signaling pathways are key mediators of sleep deprivation and that targeting these pathways could be useful in designing strategies to prevent the impact of sleep loss.

neuroscience↗

bioRxiv2021

Endoplasmic Reticulum Chaperone Genes Encode Effectors of Long-Term Memory

The mechanisms underlying memory loss associated with Alzheimers disease and related dementias (ADRD) remain unclear, and no effective treatments exist. Fundamental studies have shown that a set of transcriptional regulatory proteins of the nuclear receptor 4a (Nr4a) family serve as molecular switches for long-term memory. Here, we show that Nr4a proteins regulate the transcription of a group of genes encoding chaperones that localize to the endoplasmic reticulum (ER), which function to traffic plasticity-related proteins to the cell surface during long lasting forms of synaptic plasticity and memory. Nr4a transcription factors and ER chaperones are linked to ADRD in human samples as well as mouse models, and overexpressing Nr4a1 or the ER chaperone Hspa5 ameliorates the long-term memory deficits in a tau-based mouse model of ADRD, pointing towards novel therapeutic approaches for treating memory loss. Thus, our findings establish protein folding in the ER as a novel molecular concept underlying long-term memory, providing new insights into the mechanistic basis of cognitive deficits in dementia. One-Sentence SummaryMolecular approaches establish protein folding in the endoplasmic reticulum as a novel molecular concept underlying synaptic plasticity and memory, serving as a switch to regulate protein folding and trafficking, and driving cognitive deficits in neurodegenerative disorders.

neuroscience↗

bioRxiv2021

Mice lacking the cAMP effector protein POPDC1 show enhanced hippocampal synaptic plasticity

Extensive research has uncovered diverse forms of synaptic plasticity and a wide array of molecular signaling mechanisms that act as positive or negative regulators. Specifically, cAMP-dependent signaling pathways have been crucially implicated in long-lasting synaptic plasticity. In this study, we examine the role of POPDC1 (or BVES), a cAMP effector protein expressed in brain, in modulating hippocampal synaptic plasticity. Unlike other cAMP effectors, such as PKA and EPAC, POPDC1 is membrane-bound and the sequence of the cAMP-binding cassette differs from canonical cAMP-binding domains. These properties suggest that POPDC1 may have a unique role in cAMP-mediated signaling underlying synaptic plasticity. Our results show that POPDC1 is enriched in hippocampal synaptoneurosomes. Acute hippocampal slices from Popdc1 knockout (KO) mice exhibit enhanced long-term potentiation (LTP) induced by a variety of stimulation paradigms, particularly in response to weak stimulation paradigms that in slices from wildtype mice induce only transient LTP. Furthermore, Popdc1 KO mice did not display any further enhancement in forskolin-induced LTP observed following inhibition of phosphodiesterases (PDEs), suggesting a possible modulation of cAMP-PDE signaling by POPDC1. Taken together, these data reveal POPDC1 as a novel player in the regulation of hippocampal synaptic plasticity and as a potential target for cognitive enhancement strategies.

neuroscience↗

bioRxiv2020

Selective role of the translin/trax RNase complex in hippocampal synaptic plasticity

Activity-dependent local protein synthesis is critical for synapse-specific, persistent plasticity. Abnormalities in local protein synthesis have been implicated in psychiatric disorders. We have recently identified the translin/trax microRNA-degrading enzyme as a novel mediator of protein synthesis at activated synapses. Additionally, mice lacking translin/trax exhibit some of the behavioral abnormalities found in a mouse model of fragile X syndrome. Therefore, identifying signaling pathways interacting with translin/trax to support persistent synaptic plasticity is a translationally relevant goal. Here, as a first step to achieve this goal, we have assessed the requirement of translin/trax for multiple hippocampal synaptic plasticity paradigms that rely on distinct molecular mechanisms. We found that mice lacking translin/trax exhibited selective impairment in a form of persistent hippocampal plasticity, which requires postsynaptic PKA activity. In contrast, enduring forms of plasticity that are dependent on presynaptic PKA were unaffected. Furthermore, these mice did not display exaggerated metabotropic glutamate receptor-mediated long-term synaptic depression, a hallmark of the mouse model of fragile X syndrome. Taken together, these findings demonstrate that translin/trax mediates long-term synaptic plasticity that is dependent on postsynaptic PKA signaling.

neuroscience↗