Gephyrin Palmitoylation in Basolateral Amygdala Mediates the Anxiolytic Action of Benzodiazepine

Shen, Zu-Cheng; Wu, Pengfei; Wang, Fang; Xia, Zhi-Xuan; Deng, Qiao; Nie, Tai-Lei; Zhang, Shao-Qi; Zheng, Hongchen; Liu, Wenhui; Lu, Jia-Jing; Gao, Shuang-Qi; Yao, Xia-Ping; Long, Li‐Hong; Hu, Zhuang-Li; Chen, Jianguo

doi:10.1016/j.biopsych.2018.09.024

Cited by 24 publications

(14 citation statements)

References 57 publications

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“…In contrast, preventing gephyrin palmitoylation leads to non-synaptic mislocalized gephyrin clusters ( Dejanovic et al, 2014a ). Interestingly, the reduced GABAergic transmission due to the expression of a palmitoylation-deficient gephyrin mutant in the basolateral amygdala leads to severe anxiety disorders in rats ( Shen et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Tuning GABAergic Inhibition: Gephyrin Molecular Organization and Functions

et al. 2020

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To be highly reliable, synaptic transmission needs postsynaptic receptors (Rs) in precise apposition to the presynaptic release sites. At inhibitory synapses, the postsynaptic protein gephyrin self-assembles to form a scaffold that anchors glycine and GABA A Rs to the cytoskeleton, thus ensuring the accurate accumulation of postsynaptic receptors at the right place. This protein undergoes several post-translational modifications which control protein–protein interaction and downstream signaling pathways. In addition, through the constant exchange of scaffolding elements and receptors in and out of synapses, gephyrin dynamically regulates synaptic strength and plasticity. The aim of the present review is to highlight recent findings on the functional role of gephyrin at GABAergic inhibitory synapses. We will discuss different approaches used to interfere with gephyrin in order to unveil its function. In addition, we will focus on the impact of gephyrin structure and distribution at the nanoscale level on the functional properties of inhibitory synapses as well as the implications of this scaffold protein in synaptic plasticity processes. Finally, we will emphasize how gephyrin genetic mutations or alterations in protein expression levels are implicated in several neuropathological disorders, including autism spectrum disorders, schizophrenia, temporal lobe epilepsy and Alzheimer's disease, all associated with severe deficits of GABAergic signaling. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.

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Section: Introductionmentioning

confidence: 99%

Tuning GABAergic Inhibition: Gephyrin Molecular Organization and Functions

et al. 2020

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“…GABA A R, but not iGluRs, is the substrate of PPT1 Numerous studies have demonstrated that both GABA A R [19][20][21] and gephyrin [22,43] are palmitoylated proteins. Palmitoylation regulates the clustering and cell surface stability of GABA A R [19].…”

Section: Discussionmentioning

confidence: 99%

PPT1 Deficiency-Induced GABAAR Hyperpalmitoylation Impairs Synaptic Transmission and Memory Formation

Tong

Gao

Feng

et al. 2022

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Palmitoylation is a reversible and dynamic process involving addition of palmitic acid to cysteine residues of proteins. Studies have indicated that a variety of neuronal receptors, including glutamate receptors such as AMPAR, NMDAR, and GABAAR, are palmitoylated, which contributes to the dynamic modulation of synaptic strength in response to neuronal activity. However, little is known about the depalmitoylation of these receptors. In this study, we adopted PPT1-deficient mice, an animal model that closely mimics human disease of infantile neuronal ceroid lipofuscinosis (INCLs), by knocking in a CLN1 c.451C > T nonsense mutation. We identified for the first time that the GABAARα1 subunit rather than AMPAR is the substrate of PPT1. In PPT1-deficient mice, we found the excessive palmitoylation and extended membrane location of GABAAR. Miniature inhibitory postsynaptic current (mIPSC) recorded from CA1 pyramidal neurons of PPT1-KI mice was also enhanced without disturbance of excitatory neuronal transmission. Spatial learning and memory deficits with enhancement of γ oscillation while attenuation of phase coupling was shown in the mice at as early as 2-month-old. Application of N-tert-butylhydroxylamine hydrochloride, a thioesterase mimetic, attenuated PPT1 mutation-induced GABAAR hyperpalmitoylation and its membrane accumulation with improved neuronal transmission and memory functions in the mice. These data provide new insights into the mechanisms of neuronal disorder caused by depalmitoylation deficiency and offer a clue for further intervention for INCLs and other neurodegenerative diseases.

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“…Numerous studies have demonstrated that both GABA A R [19][20][21] and gephyrin [22,68] are palmitoylated proteins. Palmitoylation regulates the clustering and cell surface stability of GABA A R [19].…”

Section: Discussionmentioning

confidence: 99%

PPT1 Deficiency-Induced GABA <sub>A</sub>R Hyperpalmitoylation Impairs Synaptic Transmission and Memory Formation

et al. 2021

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Background: Palmitoylation is a reversible and dynamic process involving addition of palmitic acid to cysteine residues of proteins. Studies have indicated that a variety of neuronal receptors, including glutamate receptors such as AMPAR, NMDAR, and GABA A R, are palmitoylated, which contributes to the dynamic modulation of synaptic strength in response to neuronal activity. However, little is known about the depalmitoylation of these receptors.Methods: A mouse model with a lost function mutation knock-in of palmitoyl protein thioesterase 1 (PPT1), an important enzyme for depalmitoylation, was employed to mimic human disease of infantile neuronal ceroid lipofuscinosis (INCLs). Immuno uorescent staining, Western blotting, biochemical assays, electrophysiological recording and behavioural tests were used to measure the effects of PPT1 de ciency.Results: We identi ed for the rst time that the GABA A Rα1 subunit rather than AMPAR is the substrate of PPT1. In PPT1-de cient mice, excessive palmitoylation and extended membrane location of GABA A R were detected. Simultaneously, spatial learning and memory de cits with dysregulation of neuronal network γ oscillation and impairment of long-term plasticity were shown in the mice at as early as 2month-old. Application of N-tert-butylhydroxylamine hydrochloride, a thioesterase mimetic, attenuated PPT1 mutation-induced GABA A R hyper-palmitoylation and its membrane accumulation with improved neuronal transmission and memory functions in the mice.Conclusions: These data provide new insights into the mechanisms of neuronal disorder caused by depalmitoylation de ciency and offer a clue for further intervention for INCLs and other neurodegenerative diseases.

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Gephyrin Palmitoylation in Basolateral Amygdala Mediates the Anxiolytic Action of Benzodiazepine

Cited by 24 publications

References 57 publications

Tuning GABAergic Inhibition: Gephyrin Molecular Organization and Functions

Tuning GABAergic Inhibition: Gephyrin Molecular Organization and Functions

PPT1 Deficiency-Induced GABAAR Hyperpalmitoylation Impairs Synaptic Transmission and Memory Formation

PPT1 Deficiency-Induced GABA <sub>A</sub>R Hyperpalmitoylation Impairs Synaptic Transmission and Memory Formation

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