Dataset Information

Specific knockdown of hippocampal astroglial EphB2 improves synaptic function via inhibition of D-serine secretion in APP/PS1 mice.

ABSTRACT: Increasing evidence emphasizes the protective role of Eph receptors in synaptic function in the pathological development of Alzheimer's disease (AD); however, their roles in the regulation of hippocampal astrocytes remain largely unknown. Here, we directly investigated the function of astroglial EphB2 on synaptic plasticity in APP/PS1 mice. Using cell isolation and transgene technologies, we first isolated hippocampal astrocytes and evaluated the expression levels of ephrinB ligands and EphB receptors. Then, we stereotaxically injected EphB2-Flox-AAV into the hippocampus of GFAP-cre/APP/PS1 mice and further evaluated hippocampal synaptic plasticity and astroglial function. Interestingly, astrocytic EphB2 expression was significantly increased in APP/PS1 mice in contrast to its expression profile in neurons. Moreover, depressing this astroglial EphB2 upregulation enhanced hippocampal synaptic plasticity, which results from harmful D-serine release. These results provide evidence of the different expression profiles and function of EphB2 between astrocytes and neurons in AD pathology.

SUBMITTER: Qi L

PROVIDER: S-EPMC6413293 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Specific knockdown of hippocampal astroglial EphB2 improves synaptic function via inhibition of D-serine secretion in APP/PS1 mice.

Qi Liang L Cui En-Hui EH Ji Chun-Mei CM Zhang Xiao-Bing XB Wang Ze-Ai ZA Sun Yuan-Zhao YZ Xu Jian-Chang JC Zhai Xiao-Fu XF Chen Zhong-Jun ZJ Li Jing J Zheng Jin-Yu JY Yu Ru-Tong RT

American journal of translational research 20190215 2

Increasing evidence emphasizes the protective role of Eph receptors in synaptic function in the pathological development of Alzheimer's disease (AD); however, their roles in the regulation of hippocampal astrocytes remain largely unknown. Here, we directly investigated the function of astroglial EphB2 on synaptic plasticity in APP/PS1 mice. Using cell isolation and transgene technologies, we first isolated hippocampal astrocytes and evaluated the expression levels of ephrinB ligands and EphB rec ...[more]

PMID: 30899407

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Project description:In Alzheimer's disease (AD), the severity of cognitive symptoms is better correlated with the levels of soluble amyloid-beta (A?) rather than with the deposition of fibrillar A? in amyloid plaques. In APP/PS1 mice, a murine model of AD, at 8 months of age the cerebellum is devoid of fibrillar A?, but dosage of soluble A?(1-42), the form which is more prone to aggregation, showed higher levels in this structure than in the forebrain. Aim of this study was to investigate the alterations of intrinsic membrane properties and of synaptic inputs in Purkinje cells (PCs) of the cerebellum, where only soluble A? is present. PCs were recorded by whole-cell patch-clamp in cerebellar slices from wild-type and APP/PS1 mice. In APP/PS1 PCs, evoked action potential discharge showed enhanced frequency adaptation and larger afterhyperpolarizations, indicating a reduction of the intrinsic membrane excitability. In the miniature GABAergic postsynaptic currents, the largest events were absent in APP/PS1 mice and the interspike intervals distribution was shifted to the left, but the mean amplitude and frequency were normal. The ryanodine-sensitive multivescicular release was not altered and the postsynaptic responsiveness to a GABA(A) agonist was intact. Climbing fiber postsynaptic currents were normal but their short-term plasticity was reduced in a time window of 100-800 ms. Parallel fiber postsynaptic currents and their short-term plasticity were normal. These results indicate that, in the cerebellar cortex, chronically elevated levels of soluble A?(1-42) are associated with alterations of the intrinsic excitability of PCs and with alterations of the release of GABA from interneurons and of glutamate from climbing fibers, while the release of glutamate from parallel fibers and all postsynaptic mechanisms are preserved. Thus, soluble A?(1-42) causes, in PCs, multiple functional alterations, including an impairment of intrinsic membrane properties and synapse-specific deficits, with differential consequences even in different subtypes of glutamatergic synapses.

Dataset Information

Specific knockdown of hippocampal astroglial EphB2 improves synaptic function via inhibition of D-serine secretion in APP/PS1 mice.

Publications

Specific knockdown of hippocampal astroglial EphB2 improves synaptic function via inhibition of D-serine secretion in APP/PS1 mice.

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