The role of hippocampal GluA1-containing AMPA receptors in learning and memory

The hippocampus (HPC), a brain area important for spatial learning and memory, requires concerted excitatory synaptic transmission via intrinsic and extrinsic connections. This transmission is mainly mediated by AMPA receptors. AMPA receptor subunit GluA1 knock−out (GluA1−/−) mice show distinct HPC−dependent behavioral phenotypes. These mutant mice are hyperactive, have no spatial working memory (SWM) and are impaired in the expression of experience−dependent behavioral despair. However, since GluA1−/− mice are globally lacking GluA1, the specific contribution of the HPC to these behaviors has not been investigated. I therefore examined the role of GluA1 in HPC by stereotaxically injecting recombinant adeno−associated viruses (rAAVs) to alter the GluA1 content of infected neurons. I employed two approaches. In the first approach, to elucidate the contribution of hippocampal GluA1−containing AMPA to different behaviors, GluA1−/− mice were injected with a GluA1−expressing rAAV in HPC, thereby reintroducing GluA1 into this area (knock−in approach). In the second approach, to detect behaviors requiring hippocampal GluA1−containing AMPA receptors in HPC, mice with floxed GluA1 alleles (GluA12lox/2lox mice) were stereotaxically injected with an rAAV expressing Cre−recombinase, thereby deleting GluA1 from this area (knock−out approach). After virus injection, the mice were tested in open field, rewarded alternation on the T−maze, and Porsolt forced swim test (FST). The results show that hyperactivity was abolished in mice from the knock−in approach, indicating that lack of GluA1 in HPC induces hyperactivity. Knock−in approach mice still had impaired SWM, while knock−out approach mice only had a partially impaired SWM, suggesting that hippocampal GluA1−containing AMPA receptors are necessary but not sufficient for intact SWM. Knock−out approach mice showed no experience−dependent changes in immobility in the FST, suggesting that hippocampal GluA1−containing AMPA receptors are required for the expression of learned behavioral despair in the FST. Overall, my thesis work dissected behaviors strictly dependent on hippocampal GluA1−containing AMPA receptors. Interestingly, and in contrast to what was hypothesized so far, SWM was not solely dependent on the HPC. Thus, this study further improves our understanding on the expression of HPC−dependent behavior