Transcriptional analysis of sex differences in hippocampal plasticity in the mouse
The neuronal representation of experience as stable memories requires a process termed consolidation, which engages the hippocampus. Sexual dimorphisms in the performance of a number of tasks requiring hippocampus-dependent memory formation have previously been described. These sex differences are generally attributed to gonadal hormone-mediated mechanisms which impact on neuroanatomy and modulate memory formation. At the molecular level, memory consolidation requires de novo transcription, activating the transcription factor CREB. This activation can be accomplished by a variety of signalling pathways including the CaM kinase cascade. Male mutant mice bearing a genetic deletion of CaMKK/, an element of this cascade, are impaired in spatial memory formation in the Morris water maze (MWM), and fail to activate CREB after spatial training. Remarkably, female mutants performed equally to their WT counterparts, indicating a sex-specific requirement for this kinase in spatial memory consolidation. This mutant line was used as a tool to investigate dimorphisms in the molecular mechanisms underlying memory formation. First, comparison of hippocampal transcriptional profiles between WT and CaMKK/ mutants by Affymetrix Microarray analysis identified four CaMKK/ regulated genes in males. Second, quantitative real-time PCR was used to compare hippocampal transcriptional profiles of these genes in naive males and females, and after training in two hippocampus-dependent tasks: the MWM and contextual fear conditioning (CFC). This study identified three genes with altered transcription thirty minutes after spatial training in the MWM and CFC in male mice: PSF, Gaa1 and SRp20. Naive females expressed lower levels of all three genes than naive males, and two of them (Gaa1 and SRp20) were not regulated specifically by training in these tasks at the same time point in females. The work described in this thesis has identified two male-specific molecular markers for hippocampal activity, and provided insights into sexual dimorphisms in the molecular mechanisms underlying memory consolidation.