β-Catenin signaling positively regulates glutamate uptake and metabolism in astrocytes.
Neurological disorders have been linked to abnormal excitatory neurotransmission. Perturbations in glutamate cycling can have profound impacts on normal activity, lead to excitotoxicity and neuroinflammation, and induce and/or exacerbate impairments in these diseases. Astrocytes play a key role in excitatory signaling as they both clear glutamate from the synaptic cleft and house enzymes responsible for glutamate conversion to glutamine. However, mechanisms responsible for the regulation of glutamate cycling, including the main astrocytic glutamate transporter excitatory amino acid transporter 2 (EAAT2 or GLT-1 in rodents) and glutamine synthetase (GS) which catalyzes the ATP-dependent reaction of glutamate and ammonia into glutamine, remain largely undefined.



Gain and loss of function for β-catenin in human progenitor-derived astrocyte (PDAs) was used to assess EAAT2 and GS levels by PCR, western blot, luciferase reporter assays, and chromatin immunoprecipitation (ChIP). Further, morpholinos were stereotaxically injected into C57BL/6 mice and western blots measured the protein levels of β-catenin, GLT-1, and GS.



β-Catenin, a transcriptional co-activator and the central mediator of Wnt/β-catenin signaling pathway, positively regulates EAAT2 and GS at the transcriptional level in PDAs by partnering with T cell factor 1 (TCF-1) and TCF-3, respectively. This pathway is conserved in vivo as the knockdown of β-catenin in the prefrontal cortex results in reduced GLT-1 and GS expression.



These studies confirm that β-catenin regulates key proteins responsible for excitatory glutamate neurotransmission in vitro and in vivo and reveal the therapeutic potential of β-catenin modulation in treating diseases with abnormal glutamatergic neurotransmission and excitotoxicity.
Department of Immunology and Microbiology, Rush University Medical Center, 1735 W Harrison Street, 614 Cohn, Chicago, IL, 60612, USA.
Victoria
V
Lutgen
Department of Immunology and Microbiology, Rush University Medical Center, 1735 W Harrison Street, 614 Cohn, Chicago, IL, 60612, USA.
Srinivas D
SD
Narasipura
Department of Immunology and Microbiology, Rush University Medical Center, 1735 W Harrison Street, 614 Cohn, Chicago, IL, 60612, USA.
Amit
A
Sharma
Department of Immunology and Microbiology, Rush University Medical Center, 1735 W Harrison Street, 614 Cohn, Chicago, IL, 60612, USA.
Stephanie
S
Min
Department of Immunology and Microbiology, Rush University Medical Center, 1735 W Harrison Street, 614 Cohn, Chicago, IL, 60612, USA. Lena_Al-Harthi@rush.edu.
Lena
L
Al-Harthi
D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D060172:Morpholinos / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D027342:Excitatory Amino Acid Transporter 2; D005904:Glial Fibrillary Acidic Protein; D060172:Morpholinos; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051820:TCF Transcription Factors; D051176:beta Catenin; D018698:Glutamic Acid
Excitatory amino acid transporter 2 (EAAT2); Excitotoxicity; Glia; Glutamine synthetase (GS); Neuroinflammation; β-Catenin