Whereas all mammals have one glutamate dehydrogenase gene (GLUD1), humans and apes carry an additional gene (GLUD2), which encodes an enzyme with distinct biochemical properties. We inserted a bacterial artificial chromosome containing the human GLUD2 gene into mice and analyzed the resulting changes in the transcriptome and metabolome during postnatal brain development. Effects were most pronounced early postnatally, and predominantly genes involved in neuronal development were affected. Remarkably, the effects in the transgenic mice partially parallel the transcriptome and metabolome differences seen between humans and macaques analyzed. Notably, the introduction of GLUD2 did not affect glutamate levels in mice, consistent with observations in the primates. Instead, the metabolic effects of GLUD2 center on the tricarboxylic acid cycle, suggesting that GLUD2 affects carbon flux during early brain development, possibly supporting lipid biosynthesis.human evolution | GLUD2 | brain metabolism G lutamate dehydrogenase (GDH) is a metabolic enzyme catalyzing the conversion of glutamate to α-ketoglutarate and ammonia (1). Whereas the ammonia is metabolized via the urea cycle, the α-ketoglutarate enters the tricarboxylic acid (TCA) cycle in mitochondria. Besides its metabolic role, glutamate also functions as a major excitatory neurotransmitter (2, 3).Whereas most organisms contain one copy of the GLUD gene encoding the GDH enzyme, humans and apes have two: GLUD1 and an additional gene, GLUD2, which originated by retroposition of the GLUD1 transcript after the split from apes and old world monkeys (4). Sequence analysis suggests that it is highly unlikely that GLUD2 would have contained an intact ORF and a K a /K s <1 throughout the evolution of apes without being functional (5). Moreover, positive selection has affected GLUD2 (4), including changes in amino acid residues that make it less sensitive to low pH and GTP inhibition, and resulting in a requirement for high ADP levels for allosteric activation (4, 6, 7). GLUD2 mRNA expression levels in tissues are lower than those of GLUD1, but similarly distributed across tissues. However, whereas the ancestral version of the GLUD enzyme occurs both in mitochondria and the cytoplasm, GLUD2 is specifically targeted to mitochondria (8, 9).Changes in GLUD2 properties have been suggested to reflect functional adaptation to the metabolism of the neurotransmitter glutamate in the brain (4, 10), and the fact that GLUD2 has been positively selected and maintained during ape and human evolution suggests that it may have physiological effects important for the function of ape and human brains. However, the connection between the emergence of the GLUD2 gene in the ancestors of apes and humans and changes in brain function remains elusive. To date, the only direct insights into GLUD2 function come from a rare GLUD2 mutation linked to the onset of Parkinson's disease (11) and from glioma cells carrying a mutated isocitrate dehydrogenase 1 gene (IDH1) where GLUD2 expression reverses the ...