Figure 8.

Model for LTP impairment induced by a-syn oligomers in CA1 pyramidal synapses. a, Under physiological conditions, theta-burst stimulation (TBS) induces Ca²⁺ influx through NMDA receptors into the postsynaptic cell and the activation of calmodulin (CaM). Through currently unknown mechanisms, Ca²⁺/CaM activates Ca²⁺/CaM-dependent protein kinase II (CaMKII), which modulates synaptic efficiency through phosphorylation of GluR1 subunits. In addition to prompting an enhancement in single-channel conductance, CaMKII promotes the trafficking and transient insertion of calcium-permeable AMPA receptors into the postsynaptic membrane, thought to be critical for the induction and/or stabilization of LTP. b, When exposed to a-syn oligomers, synapses lose the ability to respond to theta-burst stimulation. In resting synapses, the oligomers are able to activate, either directly or indirectly, the NMDA receptors, leading to an increase of NMDA channel contribution to transmission. This promotes a basal increase in the intracellular calcium and modulation of AMPA receptor trafficking, favoring the insertion of higher conductance calcium-permeable versus GluR2-containing AMPA receptors that facilitates basal synaptic transmission. Whenever activated by a theta-burst, the synapse is saturated and unable to recruit extra AMPA receptors, which translates into impaired long-term potentiation.