Gephyrin: a central GABAergic synapse organizer

Choii, Gayoung; Ko, Jaewon

doi:10.1038/emm.2015.5

Cited by 131 publications

(116 citation statements)

References 117 publications

(146 reference statements)

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“…The reigning model of NLGN function at inhibitory synapses purports that the interaction of gephyrin with NLGN2 via its gephyrin-binding domain enables the recruitment of GABA A receptors to the synapse (Choii and Ko, 2015; Tyagarajan and Fritschy, 2014). However, there have also been reports of gephyrin-independent mechanisms of GABA A receptor enrichment at inhibitory synapses (Lévi et al, 2004; Kneussel et al, 2001).…”

Section: Resultsmentioning

confidence: 99%

“…It has been suggested that NLGN2 functions through a direct interaction on its cytoplasmic tail with gephyrin, a scaffold protein thought to be essential for stabilizing glycine and GABA A receptors at inhibitory synapses (Choii and Ko, 2015; Tyagarajan and Fritschy, 2014). In addition, it has been proposed that collybistin, a brain-specific guanine nucleotide exchange factor (GEF), helps regulate the localization of gephyrin, and that NLGN2 is a specific activator of collybistin via a direct interaction at the proline rich region in its cytoplasmic tail (Kins et al, 2000; Poulopoulos et al, 2009; Soykan et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Distinct roles for extracellular and intracellular domains in neuroligin function at inhibitory synapses

Nguyen

Horn

Nicoll

2016

eLife

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Neuroligins (NLGNs) are postsynaptic cell adhesion molecules that interact transsynaptically with neurexins to mediate synapse development and function. NLGN2 is only at inhibitory synapses while NLGN3 is at both excitatory and inhibitory synapses. We found that NLGN3 function at inhibitory synapses in rat CA1 depends on the presence of NLGN2 and identified a domain in the extracellular region that accounted for this functional difference between NLGN2 and 3 specifically at inhibitory synapses. We further show that the presence of a cytoplasmic tail (c-tail) is indispensible, and identified two domains in the c-tail that are necessary for NLGN function at inhibitory synapses. These domains point to a gephyrin-dependent mechanism that is disrupted by an autism-associated mutation at R705 and a gephyrin-independent mechanism reliant on a putative phosphorylation site at S714. Our work highlights unique and separate roles for the extracellular and intracellular regions in specifying and carrying out NLGN function respectively.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Distinct roles for extracellular and intracellular domains in neuroligin function at inhibitory synapses

Nguyen

Horn

Nicoll

2016

eLife

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“…Excitatory and inhibitory synapses are identified postsynaptically by distinct neurotransmitter receptor, scaffolding protein, and adhesion molecule repertoires (Craig and Kang, 2007; Sheng and Kim, 2011; Ziv and Fisher-Lavie, 2014). Postsynaptic factors like Neuroligin 2 (Graf et al, 2004), Gephyrin (Choii and Ko, 2015), and Slitrk3 (Takahashi et al, 2012) organize inhibitory GABAergic synapses while LRRTMs organize excitatory synapses (Siddiqui et al, 2013; de Wit et al, 2009, 2013). Thus, postsynaptic regulation can occur by differential modulation of these factors.…”

Section: Discussionmentioning

confidence: 99%

Presynaptic LRP4 promotes synapse number and function of excitatory CNS neurons

Mosca

Luginbuhl

Wang

et al. 2017

eLife

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Precise coordination of synaptic connections ensures proper information flow within circuits. The activity of presynaptic organizing molecules signaling to downstream pathways is essential for such coordination, though such entities remain incompletely known. We show that LRP4, a conserved transmembrane protein known for its postsynaptic roles, functions presynaptically as an organizing molecule. In the Drosophila brain, LRP4 localizes to the nerve terminals at or near active zones. Loss of presynaptic LRP4 reduces excitatory (not inhibitory) synapse number, impairs active zone architecture, and abolishes olfactory attraction - the latter of which can be suppressed by reducing presynaptic GABAB receptors. LRP4 overexpression increases synapse number in excitatory and inhibitory neurons, suggesting an instructive role and a common downstream synapse addition pathway. Mechanistically, LRP4 functions via the conserved kinase SRPK79D to ensure normal synapse number and behavior. This highlights a presynaptic function for LRP4, enabling deeper understanding of how synapse organization is coordinated.DOI: http://dx.doi.org/10.7554/eLife.27347.001

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“…It is believed to function as a scaffold at inhibitory synapses, analogous its function to that of PSD-95 at glutamatergic synapses. It can bring GABA A receptors and stabilize them in the inhibitory synapses (Essrich et al, 1998; Kneussel et al, 1999; Jacob et al, 2005; Choii and Ko, 2015). Studies showed that the modulation of gephyrin was accompanied by changes in the clustering and function of GABA A receptor (Petrini et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

The Frequency-Dependent Aerobic Exercise Effects of Hypothalamic GABAergic Expression and Cardiovascular Functions in Aged Rats

Zhao

Cai

et al. 2017

Front. Aging Neurosci.

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A decline in cardiovascular modulation is a feature of the normal aging process and associated with cardiovascular diseases (CVDs) such as hypertension and stroke. Exercise training is known to promote cardiovascular adaptation in young animals and positive effects on motor and cognitive capabilities, as well as on brain plasticity for all ages in mice. Here, we examine the question of whether aerobic exercise interventions may impact the GABAergic neurons of the paraventricular nucleus (PVN) in aged rats which have been observed to have a decline in cardiovascular integration function. In the present study, young (2 months) and old (24 months) male Wistar rats were divided into young control (YC), old sedentary, old low frequency exercise (20 m/min, 60 min/day, 3 days/week, 12 weeks) and old high frequency exercise (20 m/min, 60 min/day, 5 days/week, 12 weeks). Exercise training indexes were obtained, including resting heart rate (HR), blood pressure (BP), plasma norepinephrine (NE), and heart weight (HW)-to-body weight (BW) ratios. The brain was removed and processed according to the immunofluorescence staining and western blot used to analyze the GABAergic terminal density, the proteins of GAD67, GABAA receptor and gephyrin in the PVN. There were significant changes in aged rats compared with those in the YC. Twelve weeks aerobic exercise training has volume-dependent ameliorated effects on cardiovascular parameters, autonomic nervous activities and GABAergic system functions. These data suggest that the density of GABAergic declines in the PVN is associated with imbalance in autonomic nervous activities in normal aging. Additionally, aerobic exercise can rescue aging-related an overactivity of the sympathetic nervous system and induces modifications the resting BP and HR to lower values via improving the GABAergic system in the PVN.

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Gephyrin: a central GABAergic synapse organizer

Cited by 131 publications

References 117 publications

Distinct roles for extracellular and intracellular domains in neuroligin function at inhibitory synapses

Distinct roles for extracellular and intracellular domains in neuroligin function at inhibitory synapses

Presynaptic LRP4 promotes synapse number and function of excitatory CNS neurons

The Frequency-Dependent Aerobic Exercise Effects of Hypothalamic GABAergic Expression and Cardiovascular Functions in Aged Rats

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