한빛사논문
- 조회880
Jinhu Kima,1, Seungjoon Kima,1, Hyeonho Kima,2, In-Wook Hwangb,2, Sungwon Baea, Sudeep Karkic, Dongwook Kima, Roberto Ogelmanb, Geul Bangd, Jin Young Kimd, Tommi Kajanderc, Ji Won Uma, Won Chan Ohb,3, and Jaewon Koa,3
aDepartment of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, Korea; bDepartment of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045; cInstitute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland; and dResearch Center for Bioconvergence Analysis, Korea Basic Science Institute, Ochang 305-732, Korea
1J. Kim and S. Kim contributed equally to this work.
2H.K. and I.-W.H. contributed equally to this work.
3To whom correspondence may be addressed.
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.
MDGA1, amyloid precursor protein, synaptic inhibition, neural circuit, hippocampus
논문정보
- Research article
- 2022년 01월 (BRIC 등록일 2022-01-26)
- 국내(교신)+국외 연구진
- 생명과학 > 신경생물학
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