Cargando…
Impact of a pyridazine derivative on tripartite synapse ultrastructure in hippocampus: a three-dimensional analysis
INTRODUCTION: We 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 activat...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10476950/ https://www.ncbi.nlm.nih.gov/pubmed/37671169 http://dx.doi.org/10.3389/fncel.2023.1229731 |
_version_ | 1785101042144247808 |
---|---|
author | Xu, Zan Foster, Joshua B. Lashley, Rashelle Wang, Xueqin Benson, Emily Kidd, Grahame Lin, Chien-liang Glenn |
author_facet | Xu, Zan Foster, Joshua B. Lashley, Rashelle Wang, Xueqin Benson, Emily Kidd, Grahame Lin, Chien-liang Glenn |
author_sort | Xu, Zan |
collection | PubMed |
description | INTRODUCTION: We 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. METHODS: Volume 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. RESULTS: LDN/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. DISCUSSION: This study provides direct evidence that pyridazine derivatives enhance the structural and functional plasticity of the tripartite synapse. |
format | Online Article Text |
id | pubmed-10476950 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-104769502023-09-05 Impact of a pyridazine derivative on tripartite synapse ultrastructure in hippocampus: a three-dimensional analysis Xu, Zan Foster, Joshua B. Lashley, Rashelle Wang, Xueqin Benson, Emily Kidd, Grahame Lin, Chien-liang Glenn Front Cell Neurosci Neuroscience INTRODUCTION: We 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. METHODS: Volume 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. RESULTS: LDN/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. DISCUSSION: This study provides direct evidence that pyridazine derivatives enhance the structural and functional plasticity of the tripartite synapse. Frontiers Media S.A. 2023-08-21 /pmc/articles/PMC10476950/ /pubmed/37671169 http://dx.doi.org/10.3389/fncel.2023.1229731 Text en Copyright © 2023 Xu, Foster, Lashley, Wang, Benson, Kidd and Lin. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Xu, Zan Foster, Joshua B. Lashley, Rashelle Wang, Xueqin Benson, Emily Kidd, Grahame Lin, Chien-liang Glenn Impact of a pyridazine derivative on tripartite synapse ultrastructure in hippocampus: a three-dimensional analysis |
title | Impact of a pyridazine derivative on tripartite synapse ultrastructure in hippocampus: a three-dimensional analysis |
title_full | Impact of a pyridazine derivative on tripartite synapse ultrastructure in hippocampus: a three-dimensional analysis |
title_fullStr | Impact of a pyridazine derivative on tripartite synapse ultrastructure in hippocampus: a three-dimensional analysis |
title_full_unstemmed | Impact of a pyridazine derivative on tripartite synapse ultrastructure in hippocampus: a three-dimensional analysis |
title_short | Impact of a pyridazine derivative on tripartite synapse ultrastructure in hippocampus: a three-dimensional analysis |
title_sort | impact of a pyridazine derivative on tripartite synapse ultrastructure in hippocampus: a three-dimensional analysis |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10476950/ https://www.ncbi.nlm.nih.gov/pubmed/37671169 http://dx.doi.org/10.3389/fncel.2023.1229731 |
work_keys_str_mv | AT xuzan impactofapyridazinederivativeontripartitesynapseultrastructureinhippocampusathreedimensionalanalysis AT fosterjoshuab impactofapyridazinederivativeontripartitesynapseultrastructureinhippocampusathreedimensionalanalysis AT lashleyrashelle impactofapyridazinederivativeontripartitesynapseultrastructureinhippocampusathreedimensionalanalysis AT wangxueqin impactofapyridazinederivativeontripartitesynapseultrastructureinhippocampusathreedimensionalanalysis AT bensonemily impactofapyridazinederivativeontripartitesynapseultrastructureinhippocampusathreedimensionalanalysis AT kiddgrahame impactofapyridazinederivativeontripartitesynapseultrastructureinhippocampusathreedimensionalanalysis AT linchienliangglenn impactofapyridazinederivativeontripartitesynapseultrastructureinhippocampusathreedimensionalanalysis |