Remotely controlled chemomagnetic modulation of targeted neural circuits

Rao, Siyuan; Chen, Ritchie; LaRocca, Ava A.; Christiansen, Michael G.; Senko, Alexander W.; Shi, Cindy H.; Chiang, Pai Kai; Varnavides, Georgios; Xue, Jian; Zhou, Yang; Park, Seongjun; Ding, Ruihua; Moon, Jung Hwan; Feng, Guoping; Anikeeva, Polina

doi:10.1038/s41565-019-0521-z

Cited by 93 publications

(81 citation statements)

References 33 publications

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“…However, more research is required in order to identify other residues within the γ2L and γ2S variants that are subject to phosphorylation or other PTMs, as well as how these PTMs modulate GABA A R properties. With newer tools that can achieve greater drug targeting specificity ( Shields et al, 2017 ; Atasoy and Sternson, 2018 ; Rao et al, 2019 ; Crocetti and Guerrini, 2020 ) along with rational drug design ( Antkowiak and Rammes, 2019 ; Scott and Aricescu, 2019 ), it may be possible in the near future for drug development strategies to exploit these differences in order to maximize the therapeutic efficacy of newer compounds while also decreasing the likelihood of unwanted side effects by “sparing” other GABA A R subtypes.…”

Section: Recent Advances In Gaba a R Biologymentioning

confidence: 99%

Looking for Novelty in an “Old” Receptor: Recent Advances Toward Our Understanding of GABAARs and Their Implications in Receptor Pharmacology

2021

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Diverse populations of GABAA receptors (GABAARs) throughout the brain mediate fast inhibitory transmission and are modulated by various endogenous ligands and therapeutic drugs. Deficits in GABAAR signaling underlie the pathophysiology behind neurological and neuropsychiatric disorders such as epilepsy, anxiety, and depression. Pharmacological intervention for these disorders relies on several drug classes that target GABAARs, such as benzodiazepines and more recently neurosteroids. It has been widely demonstrated that subunit composition and receptor stoichiometry impact the biophysical and pharmacological properties of GABAARs. However, current GABAAR-targeting drugs have limited subunit selectivity and produce their therapeutic effects concomitantly with undesired side effects. Therefore, there is still a need to develop more selective GABAAR pharmaceuticals, as well as evaluate the potential for developing next-generation drugs that can target accessory proteins associated with native GABAARs. In this review, we briefly discuss the effects of benzodiazepines and neurosteroids on GABAARs, their use as therapeutics, and some of the pitfalls associated with their adverse side effects. We also discuss recent advances toward understanding the structure, function, and pharmacology of GABAARs with a focus on benzodiazepines and neurosteroids, as well as newly identified transmembrane proteins that modulate GABAARs.

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Section: Recent Advances In Gaba a R Biologymentioning

confidence: 99%

Looking for Novelty in an “Old” Receptor: Recent Advances Toward Our Understanding of GABAARs and Their Implications in Receptor Pharmacology

2021

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“…Small molecules can be easily delivered to various targets, regardless of depth, but these lack the temporal precision needed to perturb cellular function on the timescales of neuronal signalling 2 . Additionally, studies evaluating use of magnetic fields to drive neuronal activation (magnetogenetics) have been controversial 4,5 and may similarly lack necessary temporal precision 6 . These reports emphasize the need for a new modality that can be used to non-invasively manipulate specific cells with millisecond precision.…”

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confidence: 99%

Sonogenetic control of mammalian cells using exogenous Transient Receptor Potential A1 channels

Duque

Lee-Kubli

Tufail

et al. 2020

Preprint

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Our understanding of the nervous system has been fundamentally advanced by light- and small molecule-sensitive proteins that can be used to modify neuronal excitability. However, optogenetics requires invasive instrumentation while chemogenetics lacks temporal control. Here, we identify a candidate channel that confers sensitivity to non-invasive ultrasound on millisecond timescales. Using a functional screen, we find that human Transient Receptor Potential A1 (hsTRPA1) increases ultrasound-evoked intracellular calcium levels and membrane potentials. Ultrasound, but not agonist, -evoked, gating of hsTRPA1, requires the N-terminal tip region, intact actin cytoskeleton, and cholesterol, implicating these features in the sonogenetic mechanism. We then use calcium imaging and electrophysiology to confirm that ultrasound-evoked responses of primary neurons are potentiated by hsTRPA1. We also show that unilateral expression of hsTRPA1 in mouse layer V motor cortical neurons leads to ultrasound-evoked contralateral limb responses to ultrasound delivered through an intact skull. Finally, ultrasound induces c-fos in hsTRPA1-expressing neurons, suggesting that our approach can be used for targeted activation of neural circuits. Together, our results demonstrate that hsTRPA1-based sonogenetics can effectively and non-invasively modulate neurons within the intact mammalian brain, a method that could be extended to other cell types across species.

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“…), light can serve as a noninvasive tool to monitor and regulate the spatiotemporal dynamics of cell signaling in living systems with a micron spatial resolution and a sub‐millisecond temporal resolution. [ 6–9 ] Currently, light has been extensively used in both fundamental research and clinical practice, such as cell signal sensing, enzyme activity monitoring, controlled drug release, visual regulation, neuromodulation, cancer diagnosis and treatment. [ 1,5,6,8,10 ]…”

Section: Near‐infrared Light and Its Biomedical Applicationsmentioning

confidence: 99%

Advanced Near‐Infrared Light for Monitoring and Modulating the Spatiotemporal Dynamics of Cell Functions in Living Systems

et al. 2020

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Light‐based technique, including optical imaging and photoregulation, has become one of the most important tools for both fundamental research and clinical practice, such as cell signal sensing, cancer diagnosis, tissue engineering, drug delivery, visual regulation, neuromodulation, and disease treatment. In particular, low energy near‐infrared (NIR, 700–1700 nm) light possesses lower phototoxicity and higher tissue penetration depth in living systems as compared with ultraviolet/visible light, making it a promising tool for in vivo applications. Currently, the NIR light‐based imaging and photoregulation strategies have offered a possibility to real‐time sense and/or modulate specific cellular events in deep tissues with subcellular accuracy. Herein, the recent progress with respect to NIR light for monitoring and modulating the spatiotemporal dynamics of cell functions in living systems are summarized. In particular, the applications of NIR light‐based techniques in cancer theranostics, regenerative medicine, and neuroscience research are systematically introduced and discussed. In addition, the challenges and prospects for NIR light‐based cell sensing and regulating techniques are comprehensively discussed.

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Remotely controlled chemomagnetic modulation of targeted neural circuits

Cited by 93 publications

References 33 publications

Looking for Novelty in an “Old” Receptor: Recent Advances Toward Our Understanding of GABAARs and Their Implications in Receptor Pharmacology

Looking for Novelty in an “Old” Receptor: Recent Advances Toward Our Understanding of GABAARs and Their Implications in Receptor Pharmacology

Sonogenetic control of mammalian cells using exogenous Transient Receptor Potential A1 channels

Advanced Near‐Infrared Light for Monitoring and Modulating the Spatiotemporal Dynamics of Cell Functions in Living Systems

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