Amyloid beta (A beta)-mediated synapse dysfunction and spine loss are considered to
be early events in Alzheimer's disease (AD) pathogenesis. N-methyl-D-aspartate receptors
(NMDARs) have previously been suggested to play a role for Amyloid beta (A beta) toxicity.
Pharmacological block of NMDAR subunits in cultured neurons and mice suggested that
NMDARs containing the GluN2B subunit are necessary for A beta-mediated changes in
synapse number and function in hippocampal neurons. Interestingly, NMDARs undergo
a developmental switch from GluN2B- to GluN2A-containing receptors. This indicates
different functional roles of NMDARs in young mice compared to older animals. In addition,
the lack of pharmacological tools to efficiently dissect the role of NMDARs containing
the different subunits complicates the interpretation of their specific role. In order
to address this problem and to investigate the specific role for A beta toxicity of
the distinct NMDAR subunits in dentate gyrus granule cells of adult mice, we used
conditional knockout mouse lines for the subunits GluN1, GluN2A and GluN2B. A beta-mediated
changes in synaptic function and neuronal anatomy were investigated in several-months
old mice with virus-mediated overproduction of A beta and in 1-year old 5xFAD mice.
We found that all three NMDAR subunits contribute to the A beta-mediated decrease
in the number of functional synapses. However, NMDARs are not required for the spine
number reduction in dentate gyrus granule cells after chronic A beta-overproduction
in 5xFAD mice. Furthermore, the amplitude of synaptic and extrasynaptic NMDAR-mediated
currents was reduced in dentate gyrus granule of 5xFAD mice without changes in current
kinetics, suggesting that a redistribution or change in subunit composition of NMDARs
does not play a role in mediating Amyloid beta (A beta) toxicity. Our study indicates
that NMDARs are involved in AD pathogenesis by compromising synapse function but not
by affecting neuron morphology.