Impact of d-serine depletion in the β-amyloid cascade related to Alzheimer’s disease

International audienceD-serine, as a co-agonist of N-methyl-D-aspartate subtype of glutamate receptors (NMDAR), is a key regulator of their activation and hence involves in functional brain plasticity and memory process. The homeostasis of these receptors is affected by soluble oligomers of the beta-amyloid peptide (Aß) in Alzheimer´s disease (AD). In the course of AD, early functional dysregulations of NMDAR are well known, even though contribution of D-serine remains so far to be determined. In 3-4 month-old transgenic mice model of amyloïdogenesis (5xFAD) showing marked increase in Aß rates and apparent unaffected D-serine levels, extracellular electrophysiological recordings reveal impaired NMDAR-dependent long-term potentiation at CA1/CA3 hippocampal synapses, without significant changes in basal synaptic transmission. This deficit persists at 12 month of age when amyloid deposits are present with concomitant disabilities in cognitive functions. Generating 5xFAD mice with depletion of D-serine (through invalidation of the synthesis enzyme: Serine Racemase), we observed that these functional alterations and the long-term behavioral impairment were prevented whereas Aßo rates remain significantly elevated and comparable to 5xAFD mice. Therefore, these results provide convincing evidence for a critical and transient involvement of D-serine in hippocampal network dysfunctions and related cognitive disabilities driven by increased amyloidogenesis