TY - JOUR
T1 - Impaired spatial memory in mice lacking CD3ζ is associated with altered NMDA and AMPA receptors signaling independent of T-Cell deficiency
AU - Louveau, Antoine
AU - Angibaud, Julie
AU - Haspot, Fabienne
AU - Opazo, Maria Cecilia
AU - Thinard, Reynald
AU - Thepenier, Virginie
AU - Baudouin, Stéphane J.
AU - Lescaudron, Laurent
AU - Hulin, Philippe
AU - Riedel, Claudia A.
AU - Boudin, Hélène
PY - 2013
Y1 - 2013
N2 - The immunoreceptor-associated protein CD3ζ is known for its role in immunity and has also been implicated in neuronal development and synaptic plasticity. However, the mechanism by which CD3ζ regulates synaptic transmission remains unclear. In this study, we showed that mice lacking CD3ζ 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 CD3ζ-/- 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 CD3ζ-/- mice did not restore spatial memory defects, suggesting that the cognitive deficits in CD3ζ-/- mice were most likely mediated through a T-cell-independent mechanism. In support of this idea, we showed that CD3ζ proteins were localized to glutamatergic postsynaptic sites, where they interacted with the NMDAR subunit GluN2A. Loss of CD3ζ 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 CD3ζ 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 CD3ζ may be mediated through its involvement in the NMDAR downstream signaling pathway leading to CaMKII-dependent LTP induction.
AB - The immunoreceptor-associated protein CD3ζ is known for its role in immunity and has also been implicated in neuronal development and synaptic plasticity. However, the mechanism by which CD3ζ regulates synaptic transmission remains unclear. In this study, we showed that mice lacking CD3ζ 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 CD3ζ-/- 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 CD3ζ-/- mice did not restore spatial memory defects, suggesting that the cognitive deficits in CD3ζ-/- mice were most likely mediated through a T-cell-independent mechanism. In support of this idea, we showed that CD3ζ proteins were localized to glutamatergic postsynaptic sites, where they interacted with the NMDAR subunit GluN2A. Loss of CD3ζ 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 CD3ζ 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 CD3ζ may be mediated through its involvement in the NMDAR downstream signaling pathway leading to CaMKII-dependent LTP induction.
UR - http://www.scopus.com/inward/record.url?scp=84887846897&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.3028-13.2013
DO - 10.1523/JNEUROSCI.3028-13.2013
M3 - Article
C2 - 24259588
AN - SCOPUS:84887846897
SN - 0270-6474
VL - 33
SP - 18672
EP - 18685
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 47
ER -