MDGA1 negatively regulates amyloid precursor protein–mediated synapse inhibition in the hippocampus

Abstract

Balanced synaptic inhibition, controlled by multiple synaptic adhesion proteins, is critical for proper brain function. MDGA1 (meprin, A-5 protein, and receptor protein-tyrosine phosphatase mu [MAM] domain-containing glycosylphosphatidylinositol anchor protein 1) suppresses synaptic inhibition in mammalian neurons, yet the molecular mechanisms underlying MDGA1-mediated negative regulation of GABAergic synapses remain unresolved. Here, we show that the MDGA1 MAM domain directly interacts with the extension domain of amyloid precursor protein (APP). Strikingly, MDGA1-mediated synaptic disinhibition requires the MDGA1 MAM domain and is prominent at distal dendrites of hippocampal CA1 pyramidal neurons. Down-regulation of APP in presynaptic GABAergic interneurons specifically suppressed GABAergic, but not glutamatergic, synaptic transmission strength and inputs onto both the somatic and dendritic compartments of hippocampal CA1 pyramidal neurons. Moreover, APP deletion manifested differential effects in somatostatin- and parvalbumin-positive interneurons in the hippocampal CA1, resulting in distinct alterations in inhibitory synapse numbers, transmission, and excitability. The infusion of MDGA1 MAM protein mimicked postsynaptic MDGA1 gain-of-function phenotypes that involve the presence of presynaptic APP. The overexpression of MDGA1 wild type or MAM, but not MAM-deleted MDGA1, in the hippocampal CA1 impaired novel object-recognition memory in mice. Thus, our results establish unique roles of APP–MDGA1 complexes in hippocampal neural circuits, providing unprecedented insight into trans-synaptic mechanisms underlying differential tuning of neuronal compartment-specific synaptic inhibition.

Functional Neuroligin-2-MDGA1 interactions differentially regulate synaptic GABAARs and cytosolic gephyrin aggregation

“…Recent data from hippocampal cultures indicated no change in mIPSC frequency or amplitude following deletion of either MDGA1 or MDGA2 (31), leading the authors to conclude that during early development, neither MDGA protein plays a role at inhibitory synapses. A further recent study in hippocampal area CA1 indicated that overexpression of WT MDGA1 and Nlgn2 binding-deficient MDGA1, but not APP binding-deficient MDGA1, causes a reduction in mIPSC frequency, while conditional deletion of MDGA1 in area CA1 had no effect on mIPSC frequency (29). These findings indicate that the effects of the MDGAs appear to depend on the experimental conditions, potentially due to differences in the ratio of MDGAs to Nlgns and other binding partners as shown previously (31).…”

“…At the same time, it was recently shown that Nlgn2 is not the only target of MDGA1, and that a transsynaptic interaction between MDGA1 and APP regulates synapse function independently of Nlgn2 at GABAergic synapses formed by oriens-lacunosum moleculare (O-LM) interneurons onto the distal dendrites of pyramidal neurons in layer S.L.M. (29). It is conceivable that the additive effects of Nlgn2 / MDGA1 dKO in layer S.R.…”

“…To determine how MDGAs may interact differentially with Nlgn2 in the regulation of GABAergic synapse function, we first used immunolabeling to assess the co-localization of MDGAs and Nlgn2 in WT mice. We focused on area CA1 in the hippocampus of adult (8-12 week old) mice (Figure 1A-B) due to the high expression level and known synaptic function of both Nlgn2 and the MDGA proteins in this region (10,24,25,29,31). Moreover, the layered structure and the precisely defined pattern of connectivity of GABAergic interneurons in area CA1 make this region uniquely suited for the study of the molecular diversity at GABAergic synapses (48).…”

“…MDGAs were proposed to negatively regulate Nlgn2 function by blocking the interaction between Nlgn2 and its presynaptic partner Nrxn, thereby potentially impairing the assembly of GABAergic synapses (21-28) (Figure 1A). Intriguingly, MDGA1 was recently shown to selectively regulate the formation of GABAergic synapses onto distal dendrites, but not proximal dendrites or somata, of hippocampal area CA1 pyramidal neurons through an interaction with presynaptic amyloid precursor protein (APP) (29). These findings support the notion that MDGAs can contribute to the diversity of GABAergic synapse function, but whether they also differentially modulate Nlgn2 function at different synapse subtypes remains completely unknown.…”

Trans‐synaptic mechanisms orchestrated by mammalian synaptic cell adhesion molecules

“…Deletion of presynaptic APP from SST + interneurons reduces the density of inhibitory synapses formed by these neurons on pyramidal neurons; this is accompanied by decreases in the release probability, synaptic strength, and excitability of these interneurons. [ 62 ] In contrast, deletion of presynaptic APP from parvalbumin + interneurons produces overall marginal phenotypes [ 62 ] (Figure 2B), hinting that APP has non‐canonical functions across different synapse types, as seen for Nrxns. [ 95 ]…”