Neurochemical Research

, Volume 44, Issue 1, pp 154–169 | Cite as

Transgenic Mice Carrying GLUD2 as a Tool for Studying the Expressional and the Functional Adaptation of this Positive Selected Gene in Human Brain Evolution

  • Andreas PlaitakisEmail author
  • Dimitra Kotzamani
  • Zoe Petraki
  • Maria Delidaki
  • Vagelis Rinotas
  • Ioannis Zaganas
  • Eleni Douni
  • Kyriaki Sidiropoulou
  • Cleanthe Spanaki
Original Paper


Human evolution is characterized by brain expansion and up-regulation of genes involved in energy metabolism and synaptic transmission, including the glutamate signaling pathway. Glutamate is the excitatory transmitter of neural circuits sub-serving cognitive functions, with glutamate-modulation of synaptic plasticity being central to learning and memory. GLUD2 is a novel positively-selected human gene involved in glutamatergic transmission and energy metabolism that underwent rapid evolutionary adaptation concomitantly with prefrontal cortex enlargement. Two evolutionary replacements (Gly456Ala and Arg443Ser) made hGDH2 resistant to GTP inhibition and allowed distinct regulation, enabling enhanced enzyme function under high glutamatergic system demands. GLUD2 adaptation may have contributed to unique human traits, but evidence for this is lacking. GLUD2 arose through retro-positioning of a processed GLUD1 mRNA to the X chromosome, a DNA replication mechanism that typically generates pseudogenes. However, by finding a suitable promoter, GLUD2 is thought to have gained expression in nerve and other tissues, where it adapted to their particular needs. Here we generated GLUD2 transgenic (Tg) mice by inserting in their genome a segment of the human X chromosome, containing the GLUD2 gene and its putative promoter. Double IF studies of Tg mouse brain revealed that the human gene is expressed in the host mouse brain in a pattern similar to that observed in human brain, thus providing credence to the above hypothesis. This expressional adaptation may have conferred novel role(s) on GLUD2 in human brain. Previous observations, also in GLUD2 Tg mice, generated and studied independently, showed that the non-redundant function of hGDH2 is markedly activated during early post-natal brain development, contributing to developmental changes in prefrontal cortex similar to those attributed to human divergence. Hence, GLUD2 adaptation may have influenced the evolutionary course taken by the human brain, but understanding the mechanism(s) involved remains challenging.


GLUD2 Transgenic mice GLUD2 Adaptation  Brain hGDH2 expression Human evolution 



Bacterial artificial chromosome


Ethylenediaminetetraacetic acid


Fluorescein isothiocyanate


Glial fibrillary acidic protein


Human glutamate dehydrogenase isoenzyme


Human glutamate dehydrogenase isoenzyme 2


Isocitrate dehydrogenase 1




Mouse glutamate dehydrogenase 1


Mitochondrial targeting sequence






Western blot


Tricarboxylic acid cycle



We are grateful to Stavros Drouboyiannis, Kostantina Mylonaki, Kostantina Aggelaki, Lambros Mathioudakis, Mara Bourbouli and Irene Skoula for their help in these studies.


This work was supported by the European Union (European Social Fund-ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF)- Research Funding Program: THALIS-UOA, Title “Mechanisms of pathogenesis of Parkinson’s disease” Grant Code (70/3/11679).


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Andreas Plaitakis
    • 1
    • 2
    Email author
  • Dimitra Kotzamani
    • 1
  • Zoe Petraki
    • 1
  • Maria Delidaki
    • 1
  • Vagelis Rinotas
    • 3
  • Ioannis Zaganas
    • 1
  • Eleni Douni
    • 3
    • 4
  • Kyriaki Sidiropoulou
    • 5
  • Cleanthe Spanaki
    • 1
  1. 1.Department of Neurology, School of MedicineUniversity of CreteHeraklionGreece
  2. 2.Neurology DepartmentIcahn School of Medicine at Mount SinaiNew YorkUSA
  3. 3.Division of ImmunologyBiomedical Sciences Research Center “Alexander Fleming”VariGreece
  4. 4.Laboratory of Genetics, Department of BiotechnologyAgricultural University of AthensAthensGreece
  5. 5.Department of BiologyUniversity of CreteHeraklionGreece

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