Impaired Spatial Memory in Mice Lacking CD3ζ Is Associated with Altered NMDA and AMPA Receptors Signaling Independent of T-Cell Deficiency

The immunoreceptor-associated protein CD3 zeta is known for its role in immunity and has also been implicated in neuronal development and synaptic plasticity. However, the mechanism by which CD3 zeta regulates synaptic transmission remains unclear. In this study, we showed that mice lacking CD3 zeta exhibited defects in spatial learning and memory as examined by the Barnes maze and object location memory tasks. Given that peripheral T cells have been shown to support cognitive functions and neural plasticity, we generated CD3 zeta(-/-) mice in which the peripheral T cells were repopulated to a normal level by syngeneic bone marrow transplantation. Using this approach, we showed that T-cell replenishment in CD3 zeta(-/-) mice did not restore spatial memory defects, suggesting that the cognitive deficits in CD3 zeta(-/-) mice were most likely mediated through a T-cell-independent mechanism. In support of this idea, we showed that CD3 zeta proteins were localized to glutamatergic postsynaptic sites, where they interacted with the NMDAR subunit GluN2A. Loss of CD3 zeta in brain decreased GluN2A-PSD95 association and GluN2A synaptic localization. This effect was accompanied by a reduced interaction of GluN2A with the key NMDAR downstream signaling protein calcium/calmodulin-dependent protein kinase II (CaMKII). Using the glycine-induced, NMDA-dependent form of chemical long-term potentiation (LTP) in cultured cortical neurons, we showed that CD3 zeta was required for activity-dependent CaMKII autophosphorylation and for the synaptic recruitment of the AMPAR subunit GluA1. Together, these results support the model that the procognitive function of CD3 zeta maybe mediated through its involvement in theNMDAR downstream signaling pathway leading to CaMKII-dependent LTP induction.