The balancing act of GABAergic synapse organizers

Ko, Jaewon; Choii, Gayoung; Um, Ji Won

doi:10.1016/j.molmed.2015.01.004

Cited by 79 publications

(59 citation statements)

References 135 publications

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“…This GABA/ glycine-induced depolarization causes a postsynaptic calcium influx that may regulate the gephyrin interactions, which is involved in the clustering of postsynaptic GABA and glycine receptors. 87,88 During maturation, developmental increases in the levels of the KCC2 co-transporter reverse this chloride gradient by the second postnatal week in rats, when GABA induces neuronal hyperpolarization. 37,77,85 Similarly, in many central synapses, both glycine and GABA receptors undergo developmental maturation themselves, which affects channel kinetics; glycine receptors, for example, shift from expressing the a2 subunit at early postnatal time-points to expressing the a1 subunit in mature neurons, shifting the functional properties of the inhibitory synapse to a faster IPSC in the second postnatal week.…”

Section: Developmental Modulation Of Inhibitory Neurotransmission In mentioning

confidence: 99%

Inhibitory neurotransmission regulates vagal efferent activity and gastric motility

McMenamin

Travagli

Browning

2016

Exp Biol Med (Maywood)

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The gastrointestinal tract receives extrinsic innervation from both the sympathetic and parasympathetic nervous systems, which regulate and modulate the function of the intrinsic (enteric) nervous system. The stomach and upper gastrointestinal tract in particular are heavily influenced by the parasympathetic nervous system, supplied by the vagus nerve, and disruption of vagal sensory or motor functions results in disorganized motility patterns, disrupted receptive relaxation and accommodation, and delayed gastric emptying, amongst others. Studies from several laboratories have shown that the activity of vagal efferent motoneurons innervating the upper GI tract is inhibited tonically by GABAergic synaptic inputs from the adjacent nucleus tractus solitarius. Disruption of this influential central GABA input impacts vagal efferent output, hence gastric functions, significantly. The purpose of this review is to describe the development, physiology, and pathophysiology of this functionally dominant inhibitory synapse and its role in regulating vagally determined gastric functions.

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Section: Developmental Modulation Of Inhibitory Neurotransmission In mentioning

confidence: 99%

Inhibitory neurotransmission regulates vagal efferent activity and gastric motility

McMenamin

Travagli

Browning

2016

Exp Biol Med (Maywood)

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“…As GABAergic inhibition is important in almost every aspect of brain physiology and the dysregulation of GABAergic synapse development has been implicated in many neurological and neuropsychiatric disorders (Ko et al, 2015; Ramamoorthi and Lin, 2011), it is critical to understand the molecular determinants of GABAergic synapse formation. Interestingly, GABAergic synapses exhibit remarkable diversity (Cherubini and Conti, 2001; Sassoe-Pognetto et al, 2011) with over twenty different types of interneurons providing domain-specific, functionally distinct GABAergic input onto principal neurons and each other (Klausberger and Somogyi, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, GABAergic synapses exhibit remarkable diversity (Cherubini and Conti, 2001; Sassoe-Pognetto et al, 2011) with over twenty different types of interneurons providing domain-specific, functionally distinct GABAergic input onto principal neurons and each other (Klausberger and Somogyi, 2008). Although many molecules and signaling pathways have been identified to regulate hippocampal GABAergic synapse development (Huang and Scheiffele, 2008; Ko et al, 2015; Krueger-Burg et al, 2017; Kuzirian and Paradis, 2011; Lu et al, 2016), a general framework for development of diverse GABAergic synapses has not been identified.…”

Section: Introductionmentioning

confidence: 99%

Molecular Dissection of Neuroligin 2 and Slitrk3 Reveals an Essential Framework for GABAergic Synapse Development

Han

Pelkey

et al. 2017

Neuron

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Summary In the brain, many types of interneurons make functionally diverse inhibitory synapses onto principal neurons. While numerous molecules have been identified to function in inhibitory synapse development, it remains unknown whether there is a unifying mechanism for development of diverse inhibitory synapses. Here we report a general molecular mechanism underlying hippocampal inhibitory synapse development. In developing neurons, the establishment of GABAergic transmission depends on Neuroligin2 (NL2), a synaptic cell adhesion molecule (CAM). During maturation, inhibitory synapse development requires both NL2 and Slitrk3 (ST3), another CAM. Importantly, NL2 and ST3 interact with nanomolar affinity through their extracellular domains to synergistically promote synapse development. Selective perturbation of the NL2-ST3 interaction impairs inhibitory synapse development with consequent disruptions in hippocampal network activity and increased seizure susceptibility. Our findings reveal how unique postsynaptic CAMs work in concert to control synaptogenesis and establish a general framework for GABAergic synapse development.

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“…The most extensively studied proteins at inhibitory synapses are arguably gephyrin and its notable binding protein, collybistin (3,4). However, although significant progress has been made, integrated principles that would allow a comprehensive understanding of inhibitory synapse organization and development, particularly at molecular levels, remain to be established (5,6).…”

mentioning

confidence: 99%

“…Gephyrin interacts with numerous other proteins whose functions at inhibitory synapses, with the exception of collybistin and neuroligin (NL) 3 -2, are largely undefined (6,9). Collybistin is required for gephyrin clustering, and their absence in mice compromises GABAergic synaptic transmission and spatial learning (10,11).…”

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confidence: 99%

IQ Motif and SEC7 Domain-containing Protein 3 (IQSEC3) Interacts with Gephyrin to Promote Inhibitory Synapse Formation

Choii

Park

et al. 2016

Journal of Biological Chemistry

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Gephyrin is a central scaffold protein that mediates development, function, and plasticity of mammalian inhibitory synapses by interacting with various inhibitory synaptic proteins. Here, we show that IQSEC3, a guanine nucleotide exchange factor for ARF6, directly interacts with gephyrin, an interaction that is critical for the inhibitory synapse localization of IQSEC3. Overexpression of IQSEC3 increases inhibitory, but not excitatory, synapse density in a guanine nucleotide exchange factor activity-dependent manner. Conversely, knockdown of IQSEC3 decreases size of gephyrin cluster without altering gephyrin puncta density. Collectively, these data reveal that IQSEC3 acts together with gephyrin to regulate inhibitory synapse development.

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The balancing act of GABAergic synapse organizers

Cited by 79 publications

References 135 publications

Inhibitory neurotransmission regulates vagal efferent activity and gastric motility

Inhibitory neurotransmission regulates vagal efferent activity and gastric motility

Molecular Dissection of Neuroligin 2 and Slitrk3 Reveals an Essential Framework for GABAergic Synapse Development

IQ Motif and SEC7 Domain-containing Protein 3 (IQSEC3) Interacts with Gephyrin to Promote Inhibitory Synapse Formation

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