PMID- 31591195 OWN - NLM STAT- MEDLINE DCOM- 20200406 LR - 20231114 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 116 IP - 43 DP - 2019 Oct 22 TI - Divergent roles of astrocytic versus neuronal EAAT2 deficiency on cognition and overlap with aging and Alzheimer's molecular signatures. PG - 21800-21811 LID - 10.1073/pnas.1903566116 [doi] AB - The excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter in the brain expressed predominantly in astrocytes and at low levels in neurons and axonal terminals. EAAT2 expression is reduced in aging and sporadic Alzheimer's disease (AD) patients' brains. The role EAAT2 plays in cognitive aging and its associated mechanisms remains largely unknown. Here, we show that conditional deletion of astrocytic and neuronal EAAT2 results in age-related cognitive deficits. Astrocytic, but not neuronal EAAT2, deletion leads to early deficits in short-term memory and in spatial reference learning and long-term memory. Neuronal EAAT2 loss results in late-onset spatial reference long-term memory deficit. Neuronal EAAT2 deletion leads to dysregulation of the kynurenine pathway, and astrocytic EAAT2 deficiency results in dysfunction of innate and adaptive immune pathways, which correlate with cognitive decline. Astrocytic EAAT2 deficiency also shows transcriptomic overlaps with human aging and AD. Overall, the present study shows that in addition to the widely recognized astrocytic EAAT2, neuronal EAAT2 plays a role in hippocampus-dependent memory. Furthermore, the gene expression profiles associated with astrocytic and neuronal EAAT2 deletion are substantially different, with the former associated with inflammation and synaptic function similar to changes observed in human AD and gene expression changes associated with inflammation similar to the aging human brain. FAU - Sharma, Abhijeet AU - Sharma A AD - Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029. AD - Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029. AD - Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029. FAU - Kazim, Syed Faraz AU - Kazim SF AD - Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029. AD - Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029. AD - Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029. FAU - Larson, Chloe S AU - Larson CS AD - Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029. AD - Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029. AD - Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029. AD - Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065. FAU - Ramakrishnan, Aarthi AU - Ramakrishnan A AD - Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029. AD - Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029. FAU - Gray, Jason D AU - Gray JD AD - Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065. FAU - McEwen, Bruce S AU - McEwen BS AD - Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065; mcewen@mail.rockefeller.edu ana.pereira@mssm.edu. FAU - Rosenberg, Paul A AU - Rosenberg PA AUID- ORCID: 0000-0002-5185-1118 AD - Department of Neurology and the F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115. AD - Program in Neuroscience, Harvard Medical School, Boston, MA 02115. FAU - Shen, Li AU - Shen L AD - Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029. AD - Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029. FAU - Pereira, Ana C AU - Pereira AC AD - Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029; mcewen@mail.rockefeller.edu ana.pereira@mssm.edu. AD - Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029. AD - Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029. LA - eng GR - R01 NS066019/NS/NINDS NIH HHS/United States GR - R01 AG063819/AG/NIA NIH HHS/United States GR - UL1 TR001866/TR/NCATS NIH HHS/United States GR - P30 HD018655/HD/NICHD NIH HHS/United States GR - R21 MH104318/MH/NIMH NIH HHS/United States GR - K76 AG054772/AG/NIA NIH HHS/United States GR - P50 MH096890/MH/NIMH NIH HHS/United States GR - U54 HD090255/HD/NICHD NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20191007 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Excitatory Amino Acid Transporter 2) RN - 0 (SLC1A2 protein, human) RN - 343-65-7 (Kynurenine) SB - IM MH - Adult MH - Aged, 80 and over MH - Aging/physiology MH - Alzheimer Disease/*metabolism MH - Animals MH - Astrocytes/*metabolism MH - Cognition/physiology MH - Cognitive Dysfunction/genetics/*pathology MH - Excitatory Amino Acid Transporter 2/*deficiency/genetics MH - Hippocampus/physiology MH - Humans MH - Kynurenine/metabolism MH - Male MH - Memory Disorders/genetics/*pathology MH - Memory, Long-Term/physiology MH - Memory, Short-Term/physiology MH - Mice MH - Mice, Knockout MH - Middle Aged MH - Neurons/*metabolism MH - Young Adult PMC - PMC6815169 OTO - NOTNLM OT - Alzheimer's disease OT - aging OT - glutamate transporter COIS- Competing interest statement: P.A.R. and D.G.C. began a collaboration in August 2019 unrelated to this research. EDAT- 2019/10/09 06:00 MHDA- 2020/04/09 06:00 PMCR- 2020/04/07 CRDT- 2019/10/09 06:00 PHST- 2019/10/09 06:00 [pubmed] PHST- 2020/04/09 06:00 [medline] PHST- 2019/10/09 06:00 [entrez] PHST- 2020/04/07 00:00 [pmc-release] AID - 1903566116 [pii] AID - 201903566 [pii] AID - 10.1073/pnas.1903566116 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2019 Oct 22;116(43):21800-21811. doi: 10.1073/pnas.1903566116. Epub 2019 Oct 7.