| First Author | Louveau A | Year | 2013 |
| Journal | J Neurosci | Volume | 33 |
| Issue | 47 | Pages | 18672-85 |
| PubMed ID | 24259588 | Mgi Jnum | J:204157 |
| Mgi Id | MGI:5529731 | Doi | 10.1523/JNEUROSCI.3028-13.2013 |
| Citation | Louveau A, et al. (2013) Impaired spatial memory in mice lacking CD3zeta is associated with altered NMDA and AMPA receptors signaling independent of T-cell deficiency. J Neurosci 33(47):18672-85 |
| abstractText | The immunoreceptor-associated protein CD3zeta is known for its role in immunity and has also been implicated in neuronal development and synaptic plasticity. However, the mechanism by which CD3zeta regulates synaptic transmission remains unclear. In this study, we showed that mice lacking CD3zeta 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 CD3zeta(-/-) 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 CD3zeta(-/-) mice did not restore spatial memory defects, suggesting that the cognitive deficits in CD3zeta(-/-) mice were most likely mediated through a T-cell-independent mechanism. In support of this idea, we showed that CD3zeta proteins were localized to glutamatergic postsynaptic sites, where they interacted with the NMDAR subunit GluN2A. Loss of CD3zeta 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 CD3zeta 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 CD3zeta may be mediated through its involvement in the NMDAR downstream signaling pathway leading to CaMKII-dependent LTP induction. |
