Author:

Abstract:

Synaptic loss is the most consistent correlate of cognitive decline in Alzheimer’s disease (AD), and AD is considered to be primary a disease of synaptic failure (Selkoe, 2002). Accordingly, several studies with mouse models of AD reported an impairment of long-termpotentiation (LTP), the main candidate mechanism for the formation of memories at the synaptic level. However, in other AD mouse models, LTP was unaffected, notwithstanding the severity of behavioral learning and memory deficits. In an effort to characterize the putative ‘synaptic failure’ in such mouse models more comprehensively, we focused on depotentiation (DP), a reversal of long-term potentiation (LTP) briefly after its induction. Here we employed the hippocampal slice preparation and performed extracellular recordings from the hippocampal CA1-region of THY-Tau22 mice. These mice overexpress human 4-repeat tau mutated at sites G272V and P301S under the control of Thy1.2 promoter. LTP is unchanged in THY-Tau22 mice despite of a progressive tau pathology (Schindowski et al., 2006) and severe learning and memory deficits with an early onset (Van der Jeugd 2011). DP was induced by applying 5Hz for 8 min. When THY-Tau22 mice were inspected at an age of 12 months when tau-pathology is fully developed, DP was found to be significantly stronger compared to WT littermates. Since tau-hyperphosphorylation by GSK-3ß is considered a major mechanism of tau-pathology we applied the selective GSK3 antagonist SB216763 but could not reverse the overshoot of DP which is in contrast to the rescue of LTD by this compound (Ahmed et al. 2015). However, the opposite approach, activation of protein phosphatase 2A, the major tau phosphorylating enzyme, by sodium selenate normalized DP to WT level which is in agreement with the efficiency of sodium selenate in rescuing impaired LTD in these mice (Ahmed et al. 2015. Our results are indicative of a difference in the pathological mechanisms that underlie the changes in DP and LTD in tau22 mice. Furthermore, they point to a higher sensitivity of DP than LTP for detecting tau-mediated deficits in synaptic function.