Changes in the Interaction between Astrocyte Processes and Synaptic Terminals in the Generation of Epileptiform Activity

Zhuravleva, Z. N.; Zhuravlev, G. I.; Samokhina, Evgeniya

doi:10.1007/s11055-020-00945-8

Cited by 1 publication

(1 citation statement)

References 29 publications

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“…Previously, we found biochemical evidence that supports the notion that our pyridazine compounds may also affect tripartite synapse morphology. The tripartite synapse responds dynamically to environmental stimuli and pathological conditions ( Lushnikova et al, 2009 ; Bellesi et al, 2015 ; Zhuravleva et al, 2020 ). However, the light microscope is not sufficient for studying its morphological changes because the PAP, dendritic processes, and axonal processes have diameters below the limit of resolution ( Harris and Stevens, 1989 ; Harris et al, 1992 ; Aten et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Impact of a pyridazine derivative on tripartite synapse ultrastructure in hippocampus: a three-dimensional analysis

Xu,

Foster,

Lashley

et al. 2023

Front. Cell. Neurosci.

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IntroductionWe previously discovered a pyridazine derivative compound series that can improve cognitive functions in mouse models of Alzheimer’s disease. One of the advanced compounds from this series, LDN/OSU-0215111-M3, was selected as the preclinical development candidate. This compound activates local protein translation at the perisynaptic astrocytic process (PAP) and enhances synaptic plasticity sequentially. While biochemical evidence supports the hypothesis that the compound enhances the structural plasticity of the tripartite synapse, its direct structural impact has not been investigated.MethodsVolume electron microscopy was used to study the hippocampal tripartite synapse three-dimensional structure in 3-month-old wild-type FVB/NJ mice after LDN/OSU-0215111-M3 treatment.ResultsLDN/OSU-0215111-M3 increased the size of tertiary apical dendrites, the volume of mushroom spines, the proportion of mushroom spines containing spine apparatus, and alterations in the spine distribution across the surface area of tertiary dendrites. Compound also increased the number of the PAP interacting with the mushroom spines as well as the size of the PAP in contact with the spines. Furthermore, proteomic analysis of the isolated synaptic terminals indicated an increase in dendritic and synaptic proteins as well as suggested a possible involvement of the phospholipase D signaling pathway. To further validate that LDN/OSU-0215111-M3 altered synaptic function, electrophysiological studies showed increased long-term potentiation following compound treatment.DiscussionThis study provides direct evidence that pyridazine derivatives enhance the structural and functional plasticity of the tripartite synapse.

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