Impairments of GABAergic transmission in hippocampus mediate increased susceptibility of epilepsy in the early stage of Alzheimer's disease
© 2024. The Author(s)..
BACKGROUND: Patients with Alzheimer's disease (AD) are often co-morbid with unprovoked seizures, making clinical diagnosis and management difficult. Although it has an important role in both AD and epilepsy, abnormal γ-aminobutyric acid (GABA)ergic transmission is recognized only as a compensative change for glutamatergic damage. Neuregulin 1 (NRG1)-ErbB4 signaling can promote GABA release and suppress epileptogenesis, but its effects on cognition in AD are still controversial.
METHODS: Four-month-old APPswe/PS1dE9 mice (APP mice) were used as animal models in the early stage of AD in this study. Acute/chronic chemical-kindling epilepsy models were established with pentylenetetrazol. Electroencephalogram and Racine scores were performed to assess seizures. Behavioral tests were used to assess cognition and emotion. Electrophysiology, western blot and immunofluorescence were performed to detect the alterations in synapses, GABAergic system components and NRG1-ErbB4 signaling. Furthermore, NRG1 was administrated intracerebroventricularly into APP mice and then its antiepileptic and cognitive effects were evaluated.
RESULTS: APP mice had increased susceptibility to epilepsy and resulting hippocampal synaptic damage and cognitive impairment. Electrophysiological analysis revealed decreased GABAergic transmission in the hippocampus. This abnormal GABAergic transmission involved a reduction in the number of parvalbumin interneurons (PV+ Ins) and decreased levels of GABA synthesis and transport. We also found impaired NRG1-ErbB4 signaling which mediated by PV+ Ins loss. And NRG1 administration could effectively reduce seizures and improve cognition in four-month-old APP mice.
CONCLUSION: Our results indicated that abnormal GABAergic transmission mediated hippocampal hyperexcitability, further excitation/inhibition imbalance, and promoted epileptogenesis in the early stage of AD. Appropriate NRG1 administration could down-regulate seizure susceptibility and rescue cognitive function. Our study provided a potential direction for intervening in the co-morbidity of AD and epilepsy.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2024 |
---|---|
Erschienen: |
2024 |
Enthalten in: |
Zur Gesamtaufnahme - volume:22 |
---|---|
Enthalten in: |
Cell communication and signaling : CCS - 22(2024), 1 vom: 22. Feb., Seite 147 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Mao, Rui [VerfasserIn] |
---|
Links: |
---|
Anmerkungen: |
Date Completed 26.02.2024 Date Revised 20.03.2024 published: Electronic Citation Status MEDLINE |
---|
doi: |
10.1186/s12964-024-01528-7 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM368789063 |
---|
LEADER | 01000caa a22002652 4500 | ||
---|---|---|---|
001 | NLM368789063 | ||
003 | DE-627 | ||
005 | 20240322000234.0 | ||
007 | cr uuu---uuuuu | ||
008 | 240229s2024 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1186/s12964-024-01528-7 |2 doi | |
028 | 5 | 2 | |a pubmed24n1339.xml |
035 | |a (DE-627)NLM368789063 | ||
035 | |a (NLM)38388921 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Mao, Rui |e verfasserin |4 aut | |
245 | 1 | 0 | |a Impairments of GABAergic transmission in hippocampus mediate increased susceptibility of epilepsy in the early stage of Alzheimer's disease |
264 | 1 | |c 2024 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 26.02.2024 | ||
500 | |a Date Revised 20.03.2024 | ||
500 | |a published: Electronic | ||
500 | |a Citation Status MEDLINE | ||
520 | |a © 2024. The Author(s). | ||
520 | |a BACKGROUND: Patients with Alzheimer's disease (AD) are often co-morbid with unprovoked seizures, making clinical diagnosis and management difficult. Although it has an important role in both AD and epilepsy, abnormal γ-aminobutyric acid (GABA)ergic transmission is recognized only as a compensative change for glutamatergic damage. Neuregulin 1 (NRG1)-ErbB4 signaling can promote GABA release and suppress epileptogenesis, but its effects on cognition in AD are still controversial | ||
520 | |a METHODS: Four-month-old APPswe/PS1dE9 mice (APP mice) were used as animal models in the early stage of AD in this study. Acute/chronic chemical-kindling epilepsy models were established with pentylenetetrazol. Electroencephalogram and Racine scores were performed to assess seizures. Behavioral tests were used to assess cognition and emotion. Electrophysiology, western blot and immunofluorescence were performed to detect the alterations in synapses, GABAergic system components and NRG1-ErbB4 signaling. Furthermore, NRG1 was administrated intracerebroventricularly into APP mice and then its antiepileptic and cognitive effects were evaluated | ||
520 | |a RESULTS: APP mice had increased susceptibility to epilepsy and resulting hippocampal synaptic damage and cognitive impairment. Electrophysiological analysis revealed decreased GABAergic transmission in the hippocampus. This abnormal GABAergic transmission involved a reduction in the number of parvalbumin interneurons (PV+ Ins) and decreased levels of GABA synthesis and transport. We also found impaired NRG1-ErbB4 signaling which mediated by PV+ Ins loss. And NRG1 administration could effectively reduce seizures and improve cognition in four-month-old APP mice | ||
520 | |a CONCLUSION: Our results indicated that abnormal GABAergic transmission mediated hippocampal hyperexcitability, further excitation/inhibition imbalance, and promoted epileptogenesis in the early stage of AD. Appropriate NRG1 administration could down-regulate seizure susceptibility and rescue cognitive function. Our study provided a potential direction for intervening in the co-morbidity of AD and epilepsy | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, Non-U.S. Gov't | |
650 | 4 | |a Alzheimer's disease | |
650 | 4 | |a Cognition | |
650 | 4 | |a Epilepsy | |
650 | 4 | |a ErbB4 | |
650 | 4 | |a GABAergic transmission | |
650 | 4 | |a NRG1 | |
650 | 4 | |a Parvalbumin interneurons | |
650 | 7 | |a Receptor, ErbB-4 |2 NLM | |
650 | 7 | |a EC 2.7.10.1 |2 NLM | |
650 | 7 | |a gamma-Aminobutyric Acid |2 NLM | |
650 | 7 | |a 56-12-2 |2 NLM | |
650 | 7 | |a Neuregulin-1 |2 NLM | |
700 | 1 | |a Hu, Mengsha |e verfasserin |4 aut | |
700 | 1 | |a Liu, Xuan |e verfasserin |4 aut | |
700 | 1 | |a Ye, Lei |e verfasserin |4 aut | |
700 | 1 | |a Xu, Bingsong |e verfasserin |4 aut | |
700 | 1 | |a Sun, Min |e verfasserin |4 aut | |
700 | 1 | |a Xu, Siyi |e verfasserin |4 aut | |
700 | 1 | |a Shao, Wenxuan |e verfasserin |4 aut | |
700 | 1 | |a Tan, Yi |e verfasserin |4 aut | |
700 | 1 | |a Xu, Yun |e verfasserin |4 aut | |
700 | 1 | |a Bai, Feng |e verfasserin |4 aut | |
700 | 1 | |a Shu, Shu |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Cell communication and signaling : CCS |d 2003 |g 22(2024), 1 vom: 22. Feb., Seite 147 |w (DE-627)NLM143253794 |x 1478-811X |7 nnns |
773 | 1 | 8 | |g volume:22 |g year:2024 |g number:1 |g day:22 |g month:02 |g pages:147 |
856 | 4 | 0 | |u http://dx.doi.org/10.1186/s12964-024-01528-7 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 22 |j 2024 |e 1 |b 22 |c 02 |h 147 |