4.8 Article

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

Publisher

NATL ACAD SCIENCES
DOI: 10.1073/pnas.2115326119

Keywords

MDGA1; amyloid precursor protein; synaptic inhibition; neural circuit; hippocampus

Funding

  1. NRF - Ministry of Science, Information and Communication Technology, and Future Planning [2017M3C7A1023470, 2021R1A2C1091863]
  2. DGIST R & D Program of the Ministry of Science and ICT [21-CoE-BT-01]
  3. NIH [R01 MH 124778, R21M H126073, T32NS099042]
  4. Brain and Behavioral Research Foundation NARSAD Young Investigator Award
  5. Brain Research Foundation Seed Grant
  6. Colorado State University/University of Colorado-Pilot Collaboration Award
  7. Jane and Aatos Erkko Foundation
  8. KBSI [C060100]
  9. [2019R1A2C1 08604]
  10. National Research Foundation of Korea [2021R1A2C1091863, 2017M3C7A1023470] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)

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Balanced synaptic inhibition is crucial for brain function. MDGA1 suppresses synaptic inhibition in mammalian neurons by interacting with APP, affecting GABAergic synaptic transmission in hippocampal CA1 neurons. Down-regulation of APP specifically suppresses GABAergic transmission strength and inputs in presynaptic interneurons. Overexpression of MDGA1 impairs novel object recognition memory in mice.
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-offunction phenotypes that involve the presence of presynaptic APP. The overexpression of MDGA1 wild type or MAM, but not MAMdeleted MDGA1, in the hippocampal CA1 impaired novel objectrecognition 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.

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