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Early Chronic Memantine Treatment-Induced Transcriptomic Changes in Wild-Type and Shank2-Mutant Mice

  • Yoo, Ye-Eun1, 2
  • Lee, Seungjoon1
  • Kim, Woohyun1
  • Kim, Hyosang1
  • Chung, Changuk2
  • Ha, Seungmin2
  • Park, Jinsu3
  • Chung, Yeonseung3
  • Kang, Hyojin4
  • Kim, Eunjoon1, 2
  • 1 Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon
  • 2 Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon
  • 3 Department of Mathematical Sciences, Korea Advanced Institute of Science and Technology, Daejeon
  • 4 Division of National Supercomputing, Korea Institute of Science and Technology Information, Daejeon
Published Article
Frontiers in Molecular Neuroscience
Frontiers Media SA
Publication Date
Sep 14, 2021
DOI: 10.3389/fnmol.2021.712576
  • Neuroscience
  • Original Research


Shank2 is an excitatory postsynaptic scaffolding protein strongly implicated in autism spectrum disorders (ASDs). Shank2-mutant mice with a homozygous deletion of exons 6 and 7 (Shank2-KO mice) show decreased NMDA receptor (NMDAR) function and autistic-like behaviors at juvenile [∼postnatal day (P21)] and adult (>P56) stages that are rescued by NMDAR activation. However, at ∼P14, these mice show the opposite change – increased NMDAR function; moreover, suppression of NMDAR activity with early, chronic memantine treatment during P7–21 prevents NMDAR hypofunction and autistic-like behaviors at later (∼P21 and >P56) stages. To better understand the mechanisms underlying this rescue, we performed RNA-Seq gene-set enrichment analysis of forebrain transcriptomes from wild-type (WT) and Shank2-KO juvenile (P25) mice treated early and chronically (P7–21) with vehicle or memantine. Vehicle-treated Shank2-KO mice showed upregulation of synapse-related genes and downregulation of ribosome- and mitochondria-related genes compared with vehicle-treated WT mice. They also showed a transcriptomic pattern largely opposite that observed in ASD (reverse-ASD pattern), based on ASD-related/risk genes and cell-type–specific genes. In memantine-treated Shank2-KO mice, chromatin-related genes were upregulated; mitochondria, extracellular matrix (ECM), and actin-related genes were downregulated; and the reverse-ASD pattern was weakened compared with that in vehicle-treated Shank2-KO mice. In WT mice, memantine treatment, which does not alter NMDAR function, upregulated synaptic genes and downregulated ECM genes; memantine-treated WT mice also exhibited a reverse-ASD pattern. Therefore, early chronic treatment of Shank2-KO mice with memantine alters expression of chromatin, mitochondria, ECM, actin, and ASD-related genes.

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