Subject(s)
Cerebral Cortex , Mental Disorders , Nerve Tissue Proteins/metabolism , Animals , Animals, Newborn , Bromodeoxyuridine/metabolism , Cell Proliferation/genetics , Cerebral Cortex/cytology , Cerebral Cortex/growth & development , Cerebral Cortex/metabolism , Embryo, Mammalian , Gene Expression Regulation, Developmental/genetics , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Humans , Mental Disorders/genetics , Mental Disorders/metabolism , Mice , Mice, Transgenic , Nerve Tissue Proteins/genetics , RNA Interference/physiology , TransfectionABSTRACT
NMDA glutamate receptors have key roles in brain development, function and dysfunction. Regulatory roles of D-serine in NMDA receptor-mediated synaptic plasticity have been reported. Nonetheless, it is unclear whether and how neonatal deficits in NMDA-receptor-mediated neurotransmission affect adult brain functions and behavior. Likewise, the role of D-serine during development remains elusive. Here we report behavioral and electrophysiological deficits associated with the frontal cortex in Pick1 knockout mice, which show D-serine deficits in a neonatal- and forebrain-specific manner. The pathological manifestations observed in adult Pick1 mice are rescued by transient neonatal supplementation of D-serine, but not by a similar treatment in adulthood. These results indicate a role for D-serine in neurodevelopment and provide novel insights on how we interpret data of psychiatric genetics, indicating the involvement of genes associated with D-serine synthesis and degradation, as well as how we consider animal models with neonatal application of NMDA receptor antagonists.
