Glutamate-specific gene linked to human brain evolution enhances synaptic plasticity and cognitive processes
Cleanthe Spanaki,
Kyriaki Sidiropoulou,
Zoe Petraki,
Konstantinos Diskos,
Xanthippi Konstantoudaki,
Emmanouela Volitaki,
Konstantina Mylonaki,
Maria Savvaki,
Andreas Plaitakis
Affiliations
Cleanthe Spanaki
Department of Neurology, School of Health Sciences, University of Crete, Voutes, Iraklion, Crete, Greece; PaGNI University Hospital of Irakleio, Neurology Department, Iraklion, Crete, Greece; Corresponding author
Kyriaki Sidiropoulou
Department of Biology, University of Crete, Voutes, Iraklion, Crete, Greece; Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas (IMBB-FORTH), Iraklion, Greece
Zoe Petraki
Department of Neurology, School of Health Sciences, University of Crete, Voutes, Iraklion, Crete, Greece
Konstantinos Diskos
Department of Biology, University of Crete, Voutes, Iraklion, Crete, Greece; Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas (IMBB-FORTH), Iraklion, Greece
Xanthippi Konstantoudaki
Department of Biology, University of Crete, Voutes, Iraklion, Crete, Greece
Emmanouela Volitaki
Department of Neurology, School of Health Sciences, University of Crete, Voutes, Iraklion, Crete, Greece; Department of Biology, University of Crete, Voutes, Iraklion, Crete, Greece
Konstantina Mylonaki
Department of Neurology, School of Health Sciences, University of Crete, Voutes, Iraklion, Crete, Greece
Maria Savvaki
Department of Neurology, School of Health Sciences, University of Crete, Voutes, Iraklion, Crete, Greece
Andreas Plaitakis
Department of Neurology, School of Health Sciences, University of Crete, Voutes, Iraklion, Crete, Greece; Corresponding author
Summary: The human brain is characterized by the upregulation of synaptic, mainly glutamatergic, transmission, but its evolutionary origin(s) remain elusive. Here we approached this fundamental question by studying mice transgenic (Tg) for GLUD2, a human gene involved in glutamate metabolism that emerged in the hominoid and evolved concomitantly with brain expansion. We demonstrate that Tg mice express the human enzyme in hippocampal astrocytes and CA1-CA3 pyramidal neurons. LTP, evoked by theta-burst stimulation, is markedly enhanced in the CA3-CA1 synapses of Tg mice, with patch-clamp recordings from CA1 pyramidal neurons revealing increased sNMDA currents. LTP enhancement is blocked by D-lactate, implying that GLUD2 potentiates L-lactate-mediated astrocyte-neuron interaction. Dendritic spine density and synaptogenesis are increased in the hippocampus of Tg mice, which exhibit enhanced responses to sensory stimuli and improved performance on complex memory tasks. Hence, GLUD2 likely contributed to human brain evolution by enhancing synaptic plasticity and metabolic processes central to cognitive functions.
