Table_8_Early Chronic Memantine Treatment-Induced Transcriptomic Changes in Wild-Type and Shank2-Mutant Mice.XLSX
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.
History
References
- https://doi.org//10.1186/2040-2392-4-36
- https://doi.org//10.1016/j.jneuroim.2004.09.007
- https://doi.org//10.1002/iub.1876
- https://doi.org//10.3389/fnins.2015.00477
- https://doi.org//10.1371/currents.RRN1291
- https://doi.org//10.1038/ng.589
- https://doi.org//10.1093/hmg/ddr470
- https://doi.org//10.1126/science.aad5487
- https://doi.org//10.1523/JNEUROSCI.4178-07.2008
- https://doi.org//10.1186/1471-2105-14-128
- https://doi.org//10.1111/cge.12105
- https://doi.org//10.1261/rna.046011.114
- https://doi.org//10.1016/j.biopsych.2018.09.025
- https://doi.org//10.1038/nn.3546
- https://doi.org//10.1038/mp.2015.119
- https://doi.org//10.1016/j.cell.2011.06.013
- https://doi.org//10.1038/nature13772
- https://doi.org//10.1016/j.ceca.2021.102406
- https://doi.org//10.1002/iub.357
- https://doi.org//10.1038/s41583-019-0196-3
- https://doi.org//10.3233/JAD-170672
- https://doi.org//10.1016/B978-0-444-63486-3.00004-9
- https://doi.org//10.1016/j.spen.2020.100829
- https://doi.org//10.1016/j.nbd.2008.01.012
- https://doi.org//10.1016/j.conb.2019.04.010
- https://doi.org//10.1016/j.tcb.2011.07.003
- https://doi.org//10.15252/embj.2019104267
- https://doi.org//10.1002/dneu.22128
- https://doi.org//10.1038/ncomms6748
- https://doi.org//10.1016/j.tins.2009.11.003
- https://doi.org//10.1016/j.conb.2017.05.018
- https://doi.org//10.1038/mp.2016.24
- https://doi.org//10.1038/nprot.2008.211
- https://doi.org//10.1038/nature13908
- https://doi.org//10.12688/f1000research.4536.1
- https://doi.org//10.1038/nature10523
- https://doi.org//10.1038/nrn1517
- https://doi.org//10.1016/j.neuron.2019.05.002
- https://doi.org//10.1093/nar/gkw377
- https://doi.org//10.1371/journal.pgen.1002521
- https://doi.org//10.1371/journal.pgen.1004580
- https://doi.org//10.1016/j.cophys.2018.03.009
- https://doi.org//10.1038/ncomms8168
- https://doi.org//10.3389/fnmol.2017.00201
- https://doi.org//10.1016/j.cell.2004.11.003
- https://doi.org//10.1038/nrd1958
- https://doi.org//10.1080/14737175.2016.1204234
- https://doi.org//10.1371/journal.pone.0056639
- https://doi.org//10.1186/s13059-014-0550-8
- https://doi.org//10.1136/bcr-2018-225119
- https://doi.org//10.1038/s41386-018-0073-1
- https://doi.org//10.1371/journal.pone.0123289
- https://doi.org//10.1371/journal.pone.0013984
- https://doi.org//10.1038/s41380-021-01060-x
- https://doi.org//10.1038/ng1180
- https://doi.org//10.4161/15384101.2014.991572
- https://doi.org//10.1016/j.pnpbp.2017.11.019
- https://doi.org//10.1038/nature20612
- https://doi.org//10.1038/nmeth.4197
- https://doi.org//10.1038/mp.2015.122
- https://doi.org//10.1038/mp.2014.172
- https://doi.org//10.1093/nar/gkz1021
- https://doi.org//10.1038/nature09146
- https://doi.org//10.1038/s41593-018-0110-8
- https://doi.org//10.1016/S0140-6736(12)61480-9
- https://doi.org//10.1007/s00109-020-02018-2
- https://doi.org//10.1038/nrg3413
- https://doi.org//10.1111/jnc.13232
- https://doi.org//10.1038/nature10945
- https://doi.org//10.1126/scisignal.2005832
- https://doi.org//10.1016/j.cell.2019.12.036
- https://doi.org//10.1101/cshperspect.a005678
- https://doi.org//10.1038/nrn3156
- https://doi.org//10.12688/f1000research.7563.2
- https://doi.org//10.1016/j.brainresbull.2017.03.003
- https://doi.org//10.1073/pnas.0506580102
- https://doi.org//10.1016/j.neuroscience.2016.11.017
- https://doi.org//10.1007/s12035-020-01879-5
- https://doi.org//10.1126/science.aav8130
- https://doi.org//10.1016/j.biopsych.2019.01.020
- https://doi.org//10.1038/nature10110
- https://doi.org//10.3389/fnsyn.2010.00139
- https://doi.org//10.1038/s41467-020-18723-y
- https://doi.org//10.1038/s41380-019-0351-2
- https://doi.org//10.1038/ncomms10717
- https://doi.org//10.1146/annurev-neuro-080317-061747
- https://doi.org//10.1038/nature11208
- https://doi.org//10.1093/nar/gkr1145
- https://doi.org//10.1093/database/bay106
- https://doi.org//10.1038/nn.4524
- https://doi.org//10.1038/s41593-019-0365-8
- https://doi.org//10.1126/science.aaa1934
- https://doi.org//10.1038/s41398-021-01233-w
- https://doi.org//10.1093/hmg/ddt547