Author:

Abstract:

Alzheimer’s disease (AD) and fronto-temporal lobe dementia (FTLD) are neurodegenerative disorders characterized by memory deficits and executive dysfunction. Hyperphosphorylation of protein Tau is a primary pathogenic mechanism in AD and FTLD leading to the accumulation and distribution of neurofibrillar threads and tangles in cortex and hippocampus, resulting in disturbed neuronal activity. Glycogen synthase kinase 3 beta (GSK3β) is a major Tau-kinase. Here we examined the pathophysiological consequences of mutant human Tau (P301L) combined with increased activity of GSK3ß on neurobehavioral and synaptic read-outs. We investigated aged (12 months) double transgenic biGT mice (Terwel et al. 2008) which express constitutively active GSK3β(S9A) and mutant human Tau(P301L). biGT mice displayed contextual memory impairments, less preference for an unfamiliar conspecific in the SPSN test and reduced anxiety-like behaviors in both open field and cage activity tests test which was accompanied by increased locomotion and exploration. At the synaptic level, basal transmission was severely impaired in hippocampal area CA1, yet paired pulse ratios were unaffected across a range of stimuli, pointing towards a post-synaptic deficit. In accordance with this, two forms of NMDA-receptor mediated synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD), were severely impaired in biGT compared to control mice. Interestingly, pharmacological inhibition of GSK3β failed to rescue LTD in biGT slices, whereas activation of PP2A restored LTD. Our data demonstrate that moderately increased GSK3β activity caused hyperphosphorylation of protein tau, leading to severe synaptopathy in the absence of any significant neurodegeneration.