Biology subjects

Sateesh, S.

Publications and source records attributed to Sateesh, S..

4 recordsLinked to original sources

bioRxiv2026

Synaptic plasticity deficits via aberrant engagement of metaplasticity in the hippocampus of PS19 mice

Tauopathy is characterized by progressive synaptic failure and neuroinflammation, yet the laminar-specific nature of these disruptions remains poorly understood. We investigated hippocampal functional integrity and glial reactivity in 8-10-month-old PS19 (P301S) mice. Electrophysiological recordings in the CA1 stratum radiatum revealed an unexpected increase in basal synaptic transmission despite profound deficits in both maintenance and early induction of the LTP phase. Conversely, the dentate gyrus exhibited reduced basal transmission and impaired LTP maintenance, alongside significant paired-pulse plasticity changes not observed in CA1. Furthermore, we demonstrate that transregional metaplasticity, as driven by prior activity in the stratum oriens (SO) in a way that inhibits subsequent LTP in wild-type mice, is occluded in PS19 mice. These data suggest that the tauopathic hippocampus exists in a "metaplastic" state, which inhibits future LTP. Immunofluorescence studies revealed that while astrogliosis and microglial activation were pan-hippocampal, specific neuroinflammatory markers exhibited striking laminar specificity. Mean fluorescence intensity for the neuroinflammatory astrocyte marker C3 was significantly upregulated only in the SO, and the lysosomal marker CD68 showed heightened occupancy specifically in the SO and stratum lacunosum-moleculare. Our findings indicate that tau pathology does not affect the hippocampus uniformly. Instead, it induces region-specific shifts in synaptic efficacy and a breakdown of metaplastic control that coincides with anatomically localized neuroinflammatory signaling.

neuroscience↗

bioRxiv2026

Transregional astrocyte-dependent metaplasticity in the hippocampus

Learning-related synaptic plasticity is regulated by metaplasticity, which adjusts plasticity thresholds in an activity-dependent manner. We have previously described a heterodendritic form of metaplasticity whereby priming stimulation in stratum oriens (SO) inhibits subsequent long-term potentiation (LTP) in the neighboring stratum radiatum of the hippocampal CA1 region. Here, we report that this metaplasticity is, in fact, transregional, in that the SO priming stimulation also inhibits later LTP induction at dentate gyrus (DG) middle molecular layer (MML) synapses, both in vitro and in vivo. This effect operates across the hippocampal fissure since it occurs in the absence of CA3, thus highlighting a previously unappreciated reverse-direction and long-distance hippocampal crosstalk. Our findings demonstrate an essential role of astrocytes as SO priming elicited a sustained increase in the frequency of calcium (Ca2+) events in astrocytes in the DG MML, while the metaplasticity effect was blocked by calcium-buffering in MML astrocytes. It could be triggered by either activation of M1 muscarinic acetylcholine receptors or group II metabotropic glutamate receptors, and was critically dependent on inositol 1,4,5-trisphosphate receptor type 2 signaling. The transregional inhibition of LTP was mediated by astrocytic release of tumor necrosis factor (TNF), which likely acts in an autocrine fashion on astrocytic TNF type 1 receptors (TNFR1s). Downstream of TNF-TNFR1 signaling, the inhibition of MML LTP was mediated by the activation of GluN2B-containing N-methyl-D-aspartate receptors. Thus, a complex, bidirectional neuron-glia signaling cascade orchestrates long-distance metaplasticity across hippocampal subregions, providing a novel framework for understanding how hippocampal neuronal networks dynamically regulate plasticity thresholds across space and time. Significance StatementThis study documents the existence of a transregional metaplasticity that traverses from area CA1 to the dentate gyrus across the hippocampal fissure. This reveals a novel long-distance crosstalk within the hippocampus, in addition to the classical pathways of information transfer. This form of metaplasticity entails an essential contribution by astrocytes that integrate neuronal activity and use a complex Ca2+-dependent neuron-glia-neuron signaling cascade to dynamically regulate LTP thresholds in the hippocampal dentate gyrus.

neuroscience↗

bioRxiv2025

Differential Astrocyte-supplied NMDAR Co-Agonist for CA1 versus Dentate Gyrus Long-term Potentiation

In the hippocampus, there is a region and synapse-specific N-methyl-D-aspartate receptor (NMDAR) co-agonist preference for induction of long-term potentiation (LTP). Schaffer collateral (SC)-CA1 synapses, enriched in GluN2A-containing NMDARs, favor D-serine, while medial perforant path (MPP) to dentate gyrus (DG) synapses that are rich in GluN2B-containing NMDARs prefer glycine for LTP induction. This study investigated the role of astrocytes in providing these co-agonists. We confirmed in rat hippocampal slices that exogenous D-serine (10 {micro}M) is sufficient to restore LTP at SC-CA1 synapses blocked under astrocyte calcium (Ca2+) -clamp conditions, consistent with previous findings. However, exogenous glycine (10 M) also rescued the LTP. In contrast, at MPP-DG synapses, 100 {micro}M exogenous glycine, but not 10 {micro}M nor 100 {micro}M D-serine, restored the LTP blocked by astrocyte Ca2+-clamping. Our findings support the view that, as for serine in CA1, astrocytes are the cellular source of the glycine required for LTP induction at MPP-DG synapses.

neuroscience↗

bioRxiv2018

Translational regulation of Syngap1 by FMRP modulates NMDAR mediated signalling

SYNGAP1, a Synaptic Ras-GTPase activating protein, regulates synapse maturation during a critical developmental window. Heterozygous mutation in SYNGAP1 (SYNGAP1+/-) has been shown to cause Intellectual Disability (ID) in children. Recent studies have provided evidence for altered neuronal protein synthesis in a mouse model of Syngap1+/-. However, the molecular mechanisms behind the same is unclear. Here, we report the reduced expression of a known translation regulator, FMRP, during a specific developmental period in Syngap1+/- mice. Our results demonstrated that FMRP interacts with and regulates the translation of Syngap1 mRNA. We further show that, during development, reduced translation of FMRP and this decrease in FMRP leads to a compensatory increase of Syngap1 translation in Syngap1+/-. These developmental changes are reflected in the altered response of eEF2 phosphorylation downstream of NMDA receptor signalling. We propose a cross-talk between FMRP and SYNGAP1 mediated signalling which can also explain the compensatory effect of impaired signalling observed in Syngap1+/- mice.

neuroscience↗