Distinct pattern of tau‐induced effects in the compartments of the tripartite synapse

Abstract

AbstractBackgroundTau‐induced synaptic dysfunction is thought to play a key role in the memory decline of Alzheimer’s disease (AD). Synapses are complex multicomponent structures that – in the case of glutamatergic central synapses – are made up of presynaptic, postsynaptic and astrocytic cells that interact with one another to regulate synaptic activity and plasticity. However, since the majority of studies aimed at understanding tau‐induced synaptic impairments were performed on preparations with broadly distributed mutant tau expression, the contribution of tau’s pathological actions in particular synaptic compartments to these impairments is largely unknown.MethodIn order to restrict expression of pathological tau to presynaptic, postsynaptic and astrocytic cells at Schaffer collateral synapses in the mouse hippocampus, we developed a method using a novel tau‐expressing viral vector together with Cre recombinase‐expressing transgenic mice. Electrophysiological analysis of different forms of synaptic plasticity was performed in mouse hippocampal slices 13‐14 days after intra‐hippocampal injection.ResultExpression of mutant tau in presynaptic cells of the hippocampus lead to impairment of long‐term potentiation (LTP) and long‐term depression (LTD), as well as paired‐pulse facilitation (PPF) and synaptic fatigue (SF), but not post‐tetanic potentiation (PTP). Postsynaptic expression leads to defects in LTP, PPF and PTP, while LTD and SF were unaffected. Finally, expression of pathological tau in hippocampal astrocytes had a negative impact on LTP, PPF, PTP, SF, but not LTD.ConclusionThese results suggest that tau elevation in the different cells of the tripartite synapse could lead to a compartment‐specific electrophysiological footprint. Besides extending our knowledge regarding the action of pathological tau in AD, these results are important for the development of combinatorial therapeutic approaches effective for the various synaptic impairments.