Early markers of tau pathology in young Tau.P301L mice: synaptic plasticity, cognition and neuronal synchrony

Fronto-temporal lobe dementia (FTLD) comprises a complex set of neurodegenerative disorders, characterized not only by memory deficits but also executive dysfunctions in the early stages of the disease. Hyperphosphorylation of protein Tau is a primary pathogenic mechanism in sub-types of FTLD leading to the accumulation and distribution of neurofibrillar threads and tangles (NFTs) in prefrontal cortex (PFC) and hippocampus (HC). The synaptotoxic effects of protein Tau are proposed to alter neuronal functions before NFTs can be detected, ultimately leading to cognitive dysfunction and brain circuit-disconnections. We investigated the Tau.P301L mouse model (Terwel et al., 2008) that recapitulate tau pathology and examined the pathophysiological consequences of human Tau at synaptic, behavioral and brain connectivity levels in the early stages of disease. Because FTLD is in first instance a synaptopathy, we measured synaptic plasticity using long-term potentiation (LTP) and depression (LTD) as sensitive and most informative readouts. In addition, executive (dys)functioning was reliably assed in touchscreen boxes, which depends on nearly identical features as in human studies. Finally, the temporal correlation of blood-oxygenation-level-dependent (BOLD) fluctuations between spatially distinct areas allowed us to study impairments in functional connectivity (FC) in pre-NFT Tau.P301L transgenic mice. Our results demonstrate that PFC and HC are brain regions that are most sensitive to Tau pathology and severely affected before NFTs begin to accumulate. We observed defective (1) basal synaptic transmission in the dentate gyrus, (2) LTP in PFC and CA1 region, (3) LTD in CA1, (4) response inhibition and discrimination learning abilities and (5) reduced functional connectivity in CA1 in transgenic mice compared to wild-type control mice. In conclusion, our study provides insight into early alterations in synaptic plasticity, cognitive abilities and brain functional connectivity of Tau.P301L mice, which is proposed to be crucial for research on therapeutic strategies that target the earliest stages of this disease.

Jaar van publicatie:2016