Biology subjects

Jones, O. D.

Publications and source records attributed to Jones, O. D..

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

GLP-1 agonism alters local field potential in the lateral septum and alters operant behavior in rats

GLP-1 agonists are an emerging treatment for disorders of consumption. They are most prominent as treatments for obesity, but recent literature suggests that they are effective at reducing the consumption of all types of hedonic substances. This clearly suggests a central, cognitive, mechanism rather than a peripheral mechanism or an interaction with a single signalling pathway, but the specific site or sites for this mechanism remain to be discovered. Candidate brain regions for this reward-modulating activity have a relative paucity of GLP-1 receptors, with the exception of lateral septum, which expresses an abundance of them. In these experiments we recorded local field potential from lateral septum while animals received either saline control or the GLP-1R agonist liraglutide. We find that liraglutide significantly reduced the power of both high-frequency oscillations and theta rhythm in the lateral septum, suggesting that GLP-1R agonism changes how lateral septum communicates with its network. In addition, we show that liraglutide causes animals to wait longer to respond for reward in a differential reinforcement of low rates paradigm. Together, these results suggest that a primary region in the control of the anticonsumptive action of GLP-1 agonists is the lateral septum, and that the coding of reward by this region is a central node in the network responsible for cognition about and behaviour with respect to reward.

neuroscience↗

bioRxiv2026

Absence of homeostatic downscaling in dentate gyrus granule cells

Granule cells of the hippocampal dentate gyrus fire at exceptionally low rates in order to maintain sparse neural codes. Despite the need for granule cells to remain in such relative quiescence, the mechanisms that regulate their firing rates have not received much attention. We investigated the potential of family of mechanisms, homeostatic downscaling, that could theoretically maintain granule cell firing at preferential levels following chronically elevated activity. Surprisingly, we found no evidence of reduced synaptic input or intrinsic excitability in granule cells even after prolonged exposure to GABAA receptor blockade. In fact, we found that mini excitatory postsynaptic current frequency was elevated in granule cells after prolonged exposure to GABAA antagonists. This effect was consistent across blockers or when cell firing was driven by elevated extracellular K+, and did not rely on NMDA receptors, L-type voltage gated Ca2+ channels or thrombospondin-driven synaptogenesis. However, the magnitude of long-term potentiation was reduced at synapses onto granule cells after prolonged exposure to a GABAA antagonist in vivo. We conclude that granule cells are the first known cell type that do not display homeostatic downscaling. Instead, these cells rely on other mechanisms, including metaplasticity, to maintain their activity within optimal bounds.

neuroscience↗

bioRxiv2023

Astrocyte Ca2+ signalling mediates long-distance metaplasticity in the hippocampal CA1

Astrocytes play an increasingly recognised role in regulating synaptic plasticity, but their contribution to metaplasticity is poorly understood. We have previously described a long-distance form of metaplasticity whereby priming stimulation in stratum oriens inhibits subsequent LTP in the neighbouring stratum radiatum of the hippocampal CA1 region of both rats and mice. Using genetic and pharmacological strategies to manipulate astrocytic Ca2+ signalling, we now show this form of metaplasticity requires inositol triphosphate receptor-dependent Ca2+ release in these cells. Blocking Ca2+signalling or inositol triphosphate receptors in single radiatum astrocytes abolishes the metaplasticity at nearby synapses. We also show the relevant Ca2+release in astrocytes is driven by adenosine A2B receptors, and stimulation of these receptors elicits the metaplasticity effect both in vitro and in vivo. Further, the metaplasticity requires signalling via tumor necrosis factor, but this cytokine is required to act on astrocytes, not neurons. Instead, glutamate, acting on GluN2B-containing NMDA receptors, is the likely gliotransmitter that signals to neurons to inhibit LTP. Together these data reveal a novel role for astrocytes in hippocampal LTP regulation across broader spatiotemporal scales than previously recognised. Main pointsO_LIIn hippocampal CA1, "priming" activity inhibits subsequent LTP at synapses hundreds of microns away. C_LIO_LIThis effect requires astrocytic Ca2+signaling, and a molecular cascade involving adenosine A2B receptors, tumor necrosis factor and GluN2B-containing NMDA receptors. C_LIO_LIThe metaplasticity effect is evident in vitro and in vivo. C_LIO_LILong-distance astrocyte signaling is a mechanism for regulating neural activity over broad spatiotemporal scales. C_LI

neuroscience↗