Role of GABAA receptors in EEG activity and spatial recognition memory in aged APP and PS1 double transgenic mice

Fu, Yu; Li, Liane; Wang, Yumei; Chu, Guanghui; Kong, Xiangyang; Wang, Jianhong

doi:10.1016/j.neuint.2019.104542

Cited by 10 publications

(17 citation statements)

References 54 publications

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“…Further studies have shown that Tau accumulates predominantly in excitatory neurons rather than inhibitory neurons, not only early in the entorhinal cortex but also in areas later affected by AD ( Fu H. et al, 2019 ). These studies suggest that both Aβ and Tau can affect excitatory neurons and GABA inhibitory interneurons during AD development, probably via different mechanisms, but ultimately disturbing the balance between neuronal excitation and inhibition ( Lei et al, 2016 ; Fu Y. et al, 2019 ). High levels of Tau phosphorylation induce excessive metabolism of excitatory glutamatergic neurons and GABA inhibitory interneurons, disrupting the excitation-inhibition balance and resulting in abnormal neural network activity in TauP301L mice ( Nilsen et al, 2013 ).…”

Section: Targets To Improve Gaba Inhibitory Interneuron Activitymentioning

confidence: 97%

GABAergic Inhibitory Interneuron Deficits in Alzheimer’s Disease: Implications for Treatment

et al. 2020

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Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by severe cognitive deficits and pathologically by amyloid plaques, neuronal loss, and neurofibrillary tangles. Abnormal amyloid β-protein (Aβ) deposition in the brain is often thought of as a major initiating factor in AD neuropathology. However, gammaaminobutyric acid (GABA) inhibitory interneurons are resistant to Aβ deposition, and Aβ decreases synaptic glutamatergic transmission to decrease neural network activity. Furthermore, there is now evidence suggesting that neural network activity is aberrantly increased in AD patients and animal models due to functional deficits in and decreased activity of GABA inhibitory interneurons, contributing to cognitive deficits. Here we describe the roles played by excitatory neurons and GABA inhibitory interneurons in Aβ-induced cognitive deficits and how altered GABA interneurons regulate AD neuropathology. We also comprehensively review recent studies on how GABA interneurons and GABA receptors can be exploited for therapeutic benefit. GABA interneurons are an emerging therapeutic target in AD, with further clinical trials urgently warranted.

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Section: Targets To Improve Gaba Inhibitory Interneuron Activitymentioning

confidence: 97%

GABAergic Inhibitory Interneuron Deficits in Alzheimer’s Disease: Implications for Treatment

et al. 2020

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“…Glutamate, as an excitatory neurotransmitter, is released decarboxylated by neurons to yield the inhibitory neurotransmitter gammaaminobutyric acid (GABA) [46]. Numerous studies have shown that the level of GABA is closely associated with AD [47,48]. D-Glutamine and GABA could be putative therapeutic targets of BSTSF in AD.…”

mentioning

confidence: 99%

Integrated Metabolomic and Lipidomic Analysis Reveals the Neuroprotective Mechanisms of Bushen Tiansui Formula in an Aβ1-42-Induced Rat Model of Alzheimer’s Disease

Zhang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Bushen Tiansui Formula (BSTSF) is a traditional Chinese medicine prescription. It has been widely applied to treat Alzheimer’s disease (AD) in the clinic; however, the mechanisms underlying its effects remain largely unknown. In this study, we used a rat AD model to study the effects of BSTSF on cognitive performance, and UPLC-MS/MS-based metabolomic and lipidomic analysis was further performed to identify significantly altered metabolites in the cerebral cortices of AD rats and determine the effects of BSTSF on the metabolomic and lipidomic profiles in the cerebral cortices of these animals. The results revealed that the levels of 47 metabolites and 30 lipids primarily associated with sphingolipid metabolism, glycerophospholipid metabolism, and linoleic acid metabolism were significantly changed in the cerebral cortices of AD rats. Among the altered lipids, ceramides, phosphatidylethanolamines, lysophosphatidylethanolamines, phosphatidylcholines, lysophosphatidylcholines, phosphatidylserines, sphingomyelins, and phosphatidylglycerols showed robust changes. Moreover, 34 differential endogenous metabolites and 21 lipids, of which the levels were mostly improved in the BSTSF treatment group, were identified as potential therapeutic targets of BSTSF against AD. Our results suggest that lipid metabolism is highly dysregulated in the cerebral cortices of AD rats, and BSTSF may exert its neuroprotective mechanisms by restoring metabolic balance, including that of sphingolipid metabolism, glycerophospholipid metabolism, alanine, aspartate, and glutamate metabolism, and D-glutamine and D-glutamate metabolism. Our data may lead to a deeper understanding of the AD-associated metabolic profile and shed new light on the mechanism underlying the therapeutic effects of BSTSF.

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“…In the present study, electrophysiological recordings were used following previous experiments (17), in which EEGs were recorded from mice with GABA A intervention during Y-maze task performance (Fig. 1A).…”

Section: Methodsmentioning

confidence: 99%

“…Please see Fu et al (2019) (17) for detailed information regarding electrophysiological recordings in mice.…”

Section: Methodsmentioning

confidence: 99%

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Different correlation patterns between EEG and memory after E/I balance adjustment in normal middle-aged mice and AD model mice

Zheng

2020

Preprint

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Alzheimer’s disease (AD) is correlated with brain atrophy, neuronal loss, neurotransmitter imbalance, and cognitive decline, which also occur in normal aging. Thus, comparing the differences between normal aging and AD is of interest in order to test the accelerated aging hypothesis of AD. An imbalance between excitatory/inhibitory (E/I) neurotransmission, especially in gamma-aminobutyric acid (GABA) inhibition dysfunction, is involved in both AD and normal aging. In the present study, we performed correlation analyses between electroencephalograms (EEGs) and memory in middle-aged (∼12 months old) wild-type mice (WT) and AD model mice (APP/PS1) after E/I balance adjustment via GABAA agonist muscimol and antagonist bicuculline administration (0.1 mg/kg intraperitoneally). Specifically, EEGs of the hippocampus and prefrontal cortex were recorded during Y-maze performance. Overall, WT and AD mice showed different correlation patterns between EEG activity and behavioral memory performance. Significant correlations were observed in EEG activity across a wider range of frequency bands (2–100 Hz, except 4–8 Hz) in WT mice, but were mainly observed in low frequency bands (delta-theta, 2–8 Hz) in AD mice. In addition, muscimol and bicuculline treatment contributed to better brain function in AD mice; in contrast, bicuculline administration resulted in poorer brain function in WT mice. Thus, our study suggests that AD shows a distinct pattern of disrupted brain function, rather than accelerated aging. Importantly, this work reveals new insights into future AD treatment by influencing low-frequency EEG activity through E/I balance adjustment, thereby aiding cognitive recovery.

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Role of GABAA receptors in EEG activity and spatial recognition memory in aged APP and PS1 double transgenic mice

Cited by 10 publications

References 54 publications

GABAergic Inhibitory Interneuron Deficits in Alzheimer’s Disease: Implications for Treatment

GABAergic Inhibitory Interneuron Deficits in Alzheimer’s Disease: Implications for Treatment

Integrated Metabolomic and Lipidomic Analysis Reveals the Neuroprotective Mechanisms of Bushen Tiansui Formula in an Aβ1-42-Induced Rat Model of Alzheimer’s Disease

Different correlation patterns between EEG and memory after E/I balance adjustment in normal middle-aged mice and AD model mice

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