Driving GABAergic neurons optogenetically improves learning, reduces amyloid load and enhances autophagy in a mouse model of Alzheimer’s disease

Zhang, Zijuan; Jing, Ying; Ma, Yanyun; Duan, Dong-Xiao; Li, Bo; Hölscher, Christian; Li, Cheng; Wei, Jingwen; Gao, Aishe; Shang, Lizhi; Tao, Feng; Xing, Ying

doi:10.1016/j.bbrc.2020.03.004

Cited by 19 publications

(14 citation statements)

References 20 publications

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“…AD mouse models have provided some potential insights into the network mechanisms underlying gamma frequency impairments observed in human EEG recordings. Indeed, a number of studies in various AD mouse models have also reported gamma deficits in ex vivo slice preparations, and in vivo recordings (Driver et al, 2007 ; Iaccarino et al, 2016 ; Etter et al, 2019 ; Zhang et al, 2020 ; Arroyo-García et al, 2021 ). We add to this literature by demonstrating that KA-driven gamma oscillations in brain slices from 5xFAD mice reveal deficits at an earlier stage of disease progression, and of greater impact than cholinergically-driven gamma oscillations.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, it is widely accepted that gamma frequency stimulation of PVINs is sufficient to induce gamma oscillations, whilst their targeted inhibition suppresses it, showcasing their important role in this form of network activity (Cardin et al, 2009 ; Sohal et al, 2009 ). This has led to a number of studies using optogenetic or auditory gamma frequency stimulation of PVINs to improve network and behavioural deficits and reduce plaque burden in a number of AD mouse models, highlighting the importance of studying PVINs with regard to network dysfunction in AD (Iaccarino et al, 2016 ; Lee et al, 2018 ; Etter et al, 2019 ; Martorell et al, 2019 ; Zhang et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Resilient Hippocampal Gamma Rhythmogenesis and Parvalbumin-Expressing Interneuron Function Before and After Plaque Burden in 5xFAD Alzheimer’s Disease Model

Scott

Pelkey

Caccavano

et al. 2022

Front. Synaptic Neurosci.

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Recent studies have implicated impaired Parvalbumin Fast-Spiking Interneuron (PVIN) function as a precipitating factor underlying abnormalities in network synchrony, oscillatory rhythms, and cognition associated with Alzheimer’s disease (AD). However, a complete developmental investigation of potential gamma deficits, induced by commonly used carbachol or kainate in ex vivo slice preparations, within AD model mice is lacking. We examined gamma oscillations using field recordings in acute hippocampal slices from 5xFAD and control mice, through the period of developing pathology, starting at 3 months of age, when there is minimal plaque presence in the hippocampus, through to 12+ months of age, when plaque burden is high. In addition, we examined PVIN participation in gamma rhythms using targeted cell-attached recordings of genetically-reported PVINs, in both wild type and mutant mice. In parallel, a developmental immunohistochemical characterisation probing the PVIN-associated expression of PV and perineuronal nets (PNNs) was compared between control and 5xFAD mice. Remarkably, this comprehensive longitudinal evaluation failed to reveal any obvious correlations between PVIN deficits (electrical and molecular), circuit rhythmogenesis (gamma frequency and power), and Aβ deposits/plaque formation. By 6–12 months, 5xFAD animals have extensive plaque formation throughout the hippocampus. However, a deficit in gamma oscillatory power was only evident in the oldest 5xFAD animals (12+ months), and only when using kainate, and not carbachol, to induce the oscillations. We found no difference in PV firing or phase preference during kainate-induced oscillations in younger or older 5xFAD mice compared to control, and a reduction of PV and PNNs only in the oldest 5xFAD mice. The lack of a clear relationship between PVIN function, network rhythmicity, and plaque formation in our study highlights an unexpected resilience in PVIN function in the face of extensive plaque pathology associated with this model, calling into question the presumptive link between PVIN pathology and Alzheimer’s progression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Resilient Hippocampal Gamma Rhythmogenesis and Parvalbumin-Expressing Interneuron Function Before and After Plaque Burden in 5xFAD Alzheimer’s Disease Model

Scott

Pelkey

Caccavano

et al. 2022

Front. Synaptic Neurosci.

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“…However, the probability that abnormal neuronal activity, such as hyperexcitability directly contributes to the pathogenesis of AD has recently been proposed (Canter et al, 2016;Hijazi et al, 2020). Remarkably, it has been recently demonstrated that induction of synchronized gamma oscillation of neuronal networks by optogenetic or sensory stimulation effectively halts or reverses AD-related pathology in transgenic mice carrying AD-related human pathological genes (Iaccarino et al, 2016;Adaikkan et al, 2019;Martorell et al, 2019;Zhang et al, 2020). Several mechanisms downstream to gamma-oscillations have been identified, such as activation of brain innate immune system leading to increased phagocytic activity of microglia, together with augmented vasodilation and transcytosis across the brain endothelium contributing to the removal of pathological proteins.…”

Section: Introductionmentioning

confidence: 99%

Sensory-Evoked 40-Hz Gamma Oscillation Improves Sleep and Daily Living Activities in Alzheimer’s Disease Patients

Cimenser¹,

Hempel²,

Travers³

et al. 2021

Front. Syst. Neurosci.

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Pathological proteins contributing to Alzheimer’s disease (AD) are known to disrupt normal neuronal functions in the brain, leading to unbalanced neuronal excitatory-inhibitory tone, distorted neuronal synchrony, and network oscillations. However, it has been proposed that abnormalities in neuronal activity directly contribute to the pathogenesis of the disease, and in fact it has been demonstrated that induction of synchronized 40 Hz gamma oscillation of neuronal networks by sensory stimulation reverses AD-related pathological markers in transgenic mice carrying AD-related human pathological genes. Based on these findings, the current study evaluated whether non-invasive sensory stimulation inducing cortical 40 Hz gamma oscillation is clinically beneficial for AD patients. Patients with mild to moderate AD (n = 22) were randomized to active treatment group (n = 14; gamma sensory stimulation therapy) or to sham group (n = 8). Participants in the active treatment group received precisely timed, 40 Hz visual and auditory stimulations during eye-closed condition to induce cortical 40 Hz steady-state oscillations in 1-h daily sessions over a 6-month period. Participants in the sham group were exposed to similar sensory stimulation designed to not evoke cortical 40 Hz steady-state oscillations that are observed in the active treatment patients. During the trial, nighttime activities of the patients were monitored with continuous actigraphy recordings, and their functional abilities were measured by Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) scale. Results of this study demonstrated that 1-h daily therapy was well tolerated throughout the 6-month treatment period by all subjects. Patients receiving gamma sensory stimulation showed significantly reduced nighttime active periods, in contrast, to deterioration in sleep quality in sham group patients. Patients in the sham group also showed the expected, significant decline in ADCS-ADL scores, whereas patients in the gamma sensory stimulation group fully maintained their functional abilities over the 6-month period. These findings confirm the safe application of 40 Hz sensory stimulation in AD patients and demonstrate a high adherence to daily treatment. Furthermore, this is the first time that beneficial clinical effects of the therapy are reported, justifying expanded and longer trials to explore additional clinical benefits and disease-modifying properties of gamma sensory stimulation therapy.Clinical Trial Registration:clinicaltrials.gov, identifier: NCT03556280.

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“…Activating or suppressing GABA(A) receptors by optogenetic methods also confirmed that GABA activation at young age ameliorated Aβ pathology, suggesting early life GABA as AD treatment [ 161 ]. In another research, Zhang et al found that optogenetic stimulation of GABAergic neurons in the hippocampus of APP/PS1 mice induced autophagy, mitigated neuroinflammation, reduced Aβ fragments, and completely reversed the learning impairment [ 162 ].…”

Section: Role Of Optogenetics In Alzheimer's Disease Treatmentmentioning

confidence: 99%

Optogenetics: implications for Alzheimer’s disease research and therapy

et al. 2022

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Alzheimer’s disease (AD), a critical neurodegenerative condition, has a wide range of effects on brain activity. Synaptic plasticity and neuronal circuits are the most vulnerable in Alzheimer’s disease, but the exact mechanism is unknown. Incorporating optogenetics into the study of AD has resulted in a significant leap in this field during the last decades, kicking off a revolution in our knowledge of the networks that underpin cognitive functions. In Alzheimer's disease, optogenetics can help to reduce and reverse neural circuit and memory impairments. Here we review how optogenetically driven methods have helped expand our knowledge of Alzheimer's disease, and how optogenetic interventions hint at a future translation into therapeutic possibilities for further utilization in clinical settings. In conclusion, neuroscience has witnessed one of its largest revolutions following the introduction of optogenetics into the field.

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Driving GABAergic neurons optogenetically improves learning, reduces amyloid load and enhances autophagy in a mouse model of Alzheimer’s disease

Cited by 19 publications

References 20 publications

Resilient Hippocampal Gamma Rhythmogenesis and Parvalbumin-Expressing Interneuron Function Before and After Plaque Burden in 5xFAD Alzheimer’s Disease Model

Resilient Hippocampal Gamma Rhythmogenesis and Parvalbumin-Expressing Interneuron Function Before and After Plaque Burden in 5xFAD Alzheimer’s Disease Model

Sensory-Evoked 40-Hz Gamma Oscillation Improves Sleep and Daily Living Activities in Alzheimer’s Disease Patients

Optogenetics: implications for Alzheimer’s disease research and therapy

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