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

Authors
  • 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
Type
Published Article
Journal
Frontiers in Molecular Neuroscience
Publisher
Frontiers Media SA
Publication Date
Sep 14, 2021
Volume
14
Identifiers
DOI: 10.3389/fnmol.2021.712576
Source
Frontiers
Keywords
Disciplines
  • Neuroscience
  • Original Research
License
Green

Abstract

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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