Interaction between autism-linked MDGAs and neuroligins suppresses inhibitory synapse development

Pettem, Katherine L.; Yokomaku, Daisaku; Takahashi, Hideto; Ge, Yuan; Craig, Ann Marie

doi:10.1083/jcb.201206028

Cited by 118 publications

(168 citation statements)

References 66 publications

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“…4 (GPI)-anchor-containing members of the immunoglobulin (Ig) superfamily of adhesion molecules [23]. Their exact localizations have not been determined, but gain-and loss-of-function assays suggest that they may be localized to inhibitory synapses [21,22]. Inhibitory synapse development was suppressed by MDGA1 overexpression, whereas it was enhanced by MDGA knockdown in hippocampal neurons, suggesting that MDGAs function as negative regulators [21,22].…”

Section: Reviewmentioning

confidence: 96%

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The balancing act of GABAergic synapse organizers

Choii

2015

Trends in Molecular Medicine

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Section: Reviewmentioning

confidence: 96%

“…Two studies recently documented that the MDGAs directly interact with NL-2 but not with other NLs [21,22]. MDGA1 and MDGA2 are glycosylphosphatidylinositol Box 1.…”

Section: Synapse Formation By Synaptic Adhesion Moleculesmentioning

confidence: 99%

The balancing act of GABAergic synapse organizers

Choii

2015

Trends in Molecular Medicine

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“…Another advantage is that synapses in this model system form rapidly, within minutes to hours, reducing the duration of experiments. Similar co-culture model systems were successfully employed in the past to screen for the novel synaptogenic molecules 27,37,38 .…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Synapse Formation in a Co-culture Model Incorporating GABAergic Medium Spiny Neurons and HEK293 Cells Stably Expressing GABA<sub>A</sub> Receptors

Fuchs

Nicholson

et al. 2014

JoVE

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Inhibitory neurons act in the central nervous system to regulate the dynamics and spatio-temporal co-ordination of neuronal networks. GABA (γ-aminobutyric acid) is the predominant inhibitory neurotransmitter in the brain. It is released from the presynaptic terminals of inhibitory neurons within highly specialized intercellular junctions known as synapses, where it binds to GABA A receptors (GABA A Rs) present at the plasma membrane of the synapse-receiving, postsynaptic neurons. Activation of these GABA-gated ion channels leads to influx of chloride resulting in postsynaptic potential changes that decrease the probability that these neurons will generate action potentials.During development, diverse types of inhibitory neurons with distinct morphological, electrophysiological and neurochemical characteristics have the ability to recognize their target neurons and form synapses which incorporate specific GABA A Rs subtypes. This principle of selective innervation of neuronal targets raises the question as to how the appropriate synaptic partners identify each other.To elucidate the underlying molecular mechanisms, a novel in vitro co-culture model system was established, in which medium spiny GABAergic neurons, a highly homogenous population of neurons isolated from the embryonic striatum, were cultured with stably transfected HEK293 cell lines that express different GABA A R subtypes. Synapses form rapidly, efficiently and selectively in this system, and are easily accessible for quantification. Our results indicate that various GABA A R subtypes differ in their ability to promote synapse formation, suggesting that this reduced in vitro model system can be used to reproduce, at least in part, the in vivo conditions required for the recognition of the appropriate synaptic partners and formation of specific synapses. Here the protocols for culturing the medium spiny neurons and generating HEK293 cells lines expressing GABA A Rs are first described, followed by detailed instructions on how to combine these two cell types in co-culture and analyze the formation of synaptic contacts.

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“…Furthermore, NLGN dimerization seems to be essential for its cell-surface function 66 and for instructing the differentiation of the presynaptic terminal 122 , providing another mechanism for regulating its interactions with synaptic scaffolding molecules. Recently, the MAM domain-containing GPI anchor proteins MDGA1 and MDGA2 (which are Ig superfamily adhesion molecules) were shown to selectively bind to NLGN2 and interfere with its synaptogenic activity 123,124 (FIG. 2D).…”

Section: Gephyrin and Gabaergic Synapse Formationmentioning

confidence: 99%

Gephyrin: a master regulator of neuronal function?

2014

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The neurotransmitters GABA and glycine mediate fast synaptic inhibition by activating ligandgated chloride channels-namely, type A GABA (GABA(A)) and glycine receptors. Both types of receptors are anchored postsynaptically by gephyrin, which self-assembles into a scaffold and interacts with the cytoskeleton. Current research indicates that postsynaptic gephyrin clusters are dynamic assemblies that are held together and regulated by multiple protein-protein interactions. Moreover, post-translational modifications of gephyrin regulate the formation and plasticity of GABAergic synapses by altering the clustering properties of postsynaptic scaffolds and thereby the availability and function of receptors and other signalling molecules. Here, we discuss the formation and regulation of the gephyrin scaffold, its role in GABAergic and glycinergic synaptic function and the implications for the pathophysiology of brain disorders caused by abnormal inhibitory neurotransmission. Shiva Tyagarajan graduated as a molecular virologist at the Pennsylvania State University (USA) and later trained as a neurobiologist during his post-doctoral studies at the University of Zurich. He is currently a group leader and the research focus of his group is to elucidate molecular and cellular mechanisms that couple transcriptional and post-transcriptional programs to regulate GABAergic synaptic plasticity. 3 AbstractThe neurotransmitters GABA and glycine mediate fast synaptic inhibition by activating ligand-gated Cl  channels, namely the GABA A and glycine receptors. Both types of receptors are anchored postsynaptically by gephyrin, which self-assembles into a scaffold and interacts with the cytoskeleton. Current research indicates that gephyrin postsynaptic clusters are dynamic assemblies that are held together and regulated by multiple protein-protein interactions. Moreover, posttranslational modifications of gephyrin regulate the formation and plasticity of GABAergic synapses, by altering the clustering properties of postsynaptic scaffolds and thereby the availability and function of receptors and other signalling molecules.Here, we discuss the formation and regulation of the gephyrin scaffold, its role in GABAergic and glycinergic synaptic function and the implications for the pathophysiology of brain disorders caused by abnormal inhibitory neurotransmission.On-line summary  Gephyrin is a multi-functional protein, responsible for Moco biosynthesis in all organisms, and for postsynaptic clustering of glycine receptors and GABAA receptors in vertebrate CNS  Gephyrin forms a protein scaffold by self-assembly from trimeric complexes, which interacts with numerous, structurally different proteins, in order to form a high ordered signalling complex in glycinergic and GABAergic synapses  Gephyrin function as a scaffolding protein is regulated by alternate mRNA splicing and by multiple post-transcriptional and posttranslational modifications, which only begin to be understood.  Regulation of gephyrin scaffold by multiple signallin...

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Interaction between autism-linked MDGAs and neuroligins suppresses inhibitory synapse development

Abstract: Selective suppression of inhibitory synapses—with no effect on excitatory synapses—results from interaction of the autism- and schizophrenia-associated proteins MDGA1 and neuroligin-2 through effects on the neuroligin–neurexin pathway.

Cited by 118 publications

References 66 publications

The balancing act of GABAergic synapse organizers

The balancing act of GABAergic synapse organizers

Inhibitory Synapse Formation in a Co-culture Model Incorporating GABAergic Medium Spiny Neurons and HEK293 Cells Stably Expressing GABA<sub>A</sub> Receptors

Gephyrin: a master regulator of neuronal function?

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