1. Divergent roles of astrocytic versus neuronal EAAT2 deficiency on cognition and overlap with aging and Alzheimer's molecular signatures.
- Author
-
Sharma A, Kazim SF, Larson CS, Ramakrishnan A, Gray JD, McEwen BS, Rosenberg PA, Shen L, and Pereira AC
- Subjects
- Adult, Aged, 80 and over, Aging physiology, Animals, Cognition physiology, Cognitive Dysfunction genetics, Excitatory Amino Acid Transporter 2 genetics, Hippocampus physiology, Humans, Kynurenine metabolism, Male, Memory Disorders genetics, Memory, Long-Term physiology, Memory, Short-Term physiology, Mice, Mice, Knockout, Middle Aged, Young Adult, Alzheimer Disease metabolism, Astrocytes metabolism, Cognitive Dysfunction pathology, Excitatory Amino Acid Transporter 2 deficiency, Memory Disorders pathology, Neurons metabolism
- Abstract
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., Competing Interests: Competing interest statement: P.A.R. and D.G.C. began a collaboration in August 2019 unrelated to this research.
- Published
- 2019
- Full Text
- View/download PDF