Characterization of dorsal and ventral hippocampus contributions to context fear in a CA1-specific GluR2 KO mouse.

摘要

Calcium influx through the NMDA, AMPA and kainate subtypes of glutamate receptors can mediate synaptic plasticity. In the CA1 pyramidal layer of the hippocampus, the AMPA receptor is normally calcium impermeable due to the presence of the GluR2 subunit. In these studies, we examined knockout (KO) mice with a selective deletion of GIuR2 in CA1 neurons. These mice exhibited a 100% enhancement of long-term potentiation (LTP) in the CA1 region, but no change in long-term depression (LTD). Initial behavioral analyses (Ch. 2) demonstrated that CA1-GluR2 KOs could acquire hippocampus-independent tasks but were impaired on multiple hippocampus-dependent tasks. Their learning deficits were not due to reduced pain sensitivity, hyperactivity or altered motor function. These data indicate that enhanced UP in CA1 (mediated by AMPA receptors) is detrimental to mnemonic processing in the hippocampus. A second set of studies (Ch. 3) examined the contribution of GluR2 loss in the dorsal and ventral hippocampus (DH, VH) to the context fear conditioning deficit observed in KO mice. Pre-training lesions of the DH slowed the acquisition of context fear in wildtype (WT) and KO mice. Lesions of the VH had no effect in WTs but enhanced conditioning in GluR2 KOs. Post-training lesions of the DH and VH produced significant impairments in all mice. These data suggest that: (1) the loss of GluR2 in the VH prevents KO mice from acquiring normal levels of context fear and (2) the DH and VH both encode some aspect of context fear in WT and KO mice. In Ch. 3 we also examined the contribution of non-Hebbian UP to the GluR2 KO learning deficit. In this study, context conditioning was examined in KO mice lacking both the NMDA receptor subunit NR1 and the AMPA receptor subunit GluR2 in the CA1 region. These mice exhibit normal levels of UP in CA1 mediated completely by AMPA receptors. In contrast to the deficits observed in NR1 and GluR2 KO mice, double KOs exhibited normal levels of context fear. This suggests that increased potentiation and/or calcium influx in CA1 is responsible for the learning deficits observed in GluR2 KOs, not the presence of non-Hebbian LTP. Theoretical aspects of these results are discussed in Ch. 4 and Ch. 5.