Pumping the brakes: suppression of synapse development by MDGA–neuroligin interactions

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Highlights

  • MDGAs suppress synapse development by binding to neuroligin-occluding neurexin interaction.

  • MDGA1 and MDGA2 interact with all neuroligins with differential affinities in the physiological range.

  • In vivo loss of MDGA1 elevates inhibitory synapse numbers rendering networks resistant to excitation.

  • In vivo loss of MDGA2 elevates excitatory synapse numbers and strength.

  • MDGA1 also functions in basal progenitor aggregation in the subventricular zone.

Synapse development depends on a dynamic balance between synapse promoters and suppressors. MDGAs, immunoglobulin superfamily proteins, negatively regulate synapse development through blocking neuroligin–neurexin interactions. Recent analyses of MDGA–neuroligin complexes revealed the structural basis of this activity and indicate that MDGAs interact with all neuroligins with differential affinities. Surprisingly, analyses of mouse mutants revealed a functional divergence, with targeted mutation of Mdga1 and Mdga2 elevating inhibitory and excitatory synapses, respectively, on hippocampal pyramidal neurons. Further research is needed to determine the synapse-specific organizing properties of MDGAs in neural circuits, which may depend on relative levels and subcellular distributions of each MDGA, neuroligin and neurexin. Behavioral deficits in Mdga mutant mice support genetic links to schizophrenia and autism spectrum disorders and raise the possibility of harnessing these interactions for therapeutic purposes.

Section snippets

Overview

Solving the problem of how to develop trillions of synapses requires mechanisms capable of orchestrating the timing, number, location, structure, and molecular composition of presynaptic and postsynaptic specializations appropriate to their roles in brain circuits. Synaptic organizing proteins act as molecular codes which dictate these properties during synapse assembly and maturation through the recruitment of machinery for regulated neurotransmitter release and reception. The importance of

MDGA expression and localization

MDGAs are specifically expressed in the nervous system, at highest levels during late embryonic and postnatal stages [25,26]. MDGA1 expression is most prominent in the basilar pons, superficial cortical layers, hippocampus, olfactory bulb, amygdala, thalamic nuclei, cerebellar granule layer, spinal cord, and dorsal root and trigeminal ganglia [25, 26, 27, 28]. MDGA2 exhibits more widespread expression. Expression of both MDGAs persists into adulthood in some regions including hippocampus and

Non-synaptic functions of MDGAs

Considering their structures and expression patterns, MDGAs were initially proposed to be involved in cell migration and axon outgrowth. Indeed, MDGA1 knockdown or knockout inhibits radial migration of layer 2/3 neurons during corticogenesis, although deficits are transient as knockout neurons reach their correct laminar destinations by the first postnatal week [28,32]. Perhaps more significantly, recent data indicate an early role for MDGA1 in subventricular zone basal progenitor aggregation

Interactions of MDGAs with neuroligins

MDGAs were first shown to bind NL2 using a cell-based binding assay and to block the binding of NL2 to Nrx [12], providing a mechanistic basis for the synapse suppressing activity of MDGAs. Through further study using surface plasmon resonance and co-culture functional assays, it became clear that MDGA1 and MDGA2 can bind all NLs with differential affinities [11••], as discussed further below. The five NLs in humans (four in mice) form mostly homomeric and some heteromeric dimers at

MDGAs as suppressors of synapse development

The effects of overexpression, knockdown or knockout of MDGA1 or MDGA2 on inhibitory and excitatory synapses in hippocampal or cortical neurons are summarized in Table 2. The multiple studies [12,23••,24,26,31••] are in good agreement regarding the role of MDGA1 as a selective suppressor of inhibitory synapses through selective suppression of NL2–Nrx interaction (Figure 2a). Sparse cell knockdown or overexpression of MDGA1 increased or reduced inhibitory synapse density, respectively [12],

More than simple suppression: roles of MDGAs in brain circuits and behavior

Analyses of mutant mice suggest that MDGAs may regulate synapse properties not just in a cell-type selective but also a subcellular-domain or input selective manner. Electrophysiological and ultrastructural approaches both revealed an increase in perisomatic inhibitory synapses with no change in dendritic inhibitory synapses in Mdga1−/− CA1 pyramidal cells [24]. These findings parallel selective effects of loss of NL2 on perisomatic synapses [55]. The underlying mechanisms are not known but

Future directions

MDGAs appear to be first in a class of molecules that limit synapse development by blocking the formation of trans-synaptic organizing complexes. In an analogous manner, SALM4 suppresses excitatory synapse development by cis interaction with SALM3, thus preventing the synaptogenic formation of a SALM3 trans-synaptic complex with type IIa protein tyrosine phosphatases [56]. Not only are there suppressors of such parallel pathways but, surprisingly, there appear to be additional suppressors of

Conflict of interest statement

Nothing declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was supported by Canadian Institutes of Health Research grants Fdn 143206 and NDD-144222 ERA-NET NEURON 2015 Cofund Program under Horizon 2020 (to A.M.C.), Canada Research Chair awards (to S.A.C. and A.M.C.), an Initiative of Excellence, Cluster of Excellence BRAIN fellowship (to J.E.), and Brain Canada/NeuroDevNet and Canadian Institutes of Health Research fellowships (to Y.X.).

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