Ricerc@Sapienza

The free d-amino acid, d-aspartate, is abundant in the embryonic brain but significantly decreases after birth. Besides its
intracellular occurrence, d-aspartate is also present at extracellular level and acts as an endogenous agonist for NMDA and
mGlu5 receptors. These findings suggest that d-aspartate is a candidate signaling molecule involved in neural development,
influencing brain morphology and behaviors at adulthood. To address this issue, we generated a knockin mouse model in
which the enzyme regulating d-aspartate catabolism, d-aspartate oxidase (DDO), is expressed starting from the zygotic stage,
to enable the removal of d-aspartate in prenatal and postnatal life. In line with our strategy, we found a severe depletion of
cerebral d-aspartate levels (up to 95%), since the early stages of mouse prenatal life. Despite the loss of d-aspartate content,
Ddo knockin mice are viable, fertile, and show normal gross brain morphology at adulthood. Interestingly, early d-aspartate
depletion is associated with a selective increase in the number of parvalbumin-positive interneurons in the prefrontal cortex
and also with improved memory performance in Ddo knockin mice. In conclusion, the present data indicate for the first time
a biological significance of precocious d-aspartate in regulating mouse brain formation and function at adulthood.