β-Catenin signaling positively regulates glutamate uptake and metabolism in astrocytes.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
['Lutgen|Victoria|V|', 'Narasipura|Srinivas D|SD|', 'Sharma|Amit|A|', 'Min|Stephanie|S|', 'Al-Harthi|Lena|L|']
D000818:Animals D001253:Astrocytes D001921:Brain D002478:Cells, Cultured D047369:Chromatin Immunoprecipitation D027342:Excitatory Amino Acid Transporter 2 D005904:Glial Fibrillary Acidic Protein D018698:Glutamic Acid D006801:Humans D008297:Male D051379:Mice D060172:Morpholinos D012333:RNA, Messenger D034741:RNA, Small Interfering D015398:Signal Transduction D051820:TCF Transcription Factors D014162:Transfection D051176:beta Catenin
β-Catenin Excitotoxicity Neuroinflammation Glutamine synthetase (GS) Excitatory amino acid transporter 2 (EAAT2) Glia