Human P301L tau expression in mice alters neuronal excitability independent of neurodegeneration

Abstract

Variation in the microtubule-binding protein tau is causally implicated in numerous neurodegenerative diseases, including Alzheimer’s disease. However, the mechanisms by which such variation results in disease are not well understood. The JNPL3(P301L) mouse model mimics the effects of the P301L mutation on human tau associated with frontotemporal dementia. As previously reported, phospho-tau aggregates immunolabeled with AT8 increase with age in a rostral progression from the brainstem; however, there is relatively limited forebrain pathology by the time these animals die prematurely at approximately 1 year of age. In this study, we investigated the functional effects of P301L tau expression on electrophysiological signatures as a function of age in mice expressing P301L tau from 3 to 10 months. The P301L mice had a distinct electrophysiological phenotype of increased power in higher EEG frequency bands detected with a depth electrode in the hippocampus and, to a lesser extent, with dural surface electrodes over the frontal and parietal cortices. Significantly, this electrophysiological phenotype was present at the first recording at 3 months of age and did not differ over monthly recordings up to 9 months of age, after which point animals became moribund and were euthanized. P301L mice at 10 months of age also showed electrical synchronization to a 40 Hz tone (ASSR) that was not observed in WT mice and an increase in inter-trial coherence compared with WT mice. We confirmed that AT8, as well as markers of neuroinflammation, increased progressively with age from the hindbrain to the forebrain, as previously reported. Together, these data suggest an increase in neuronal excitability in P301L mice compared with WT, but that this phenotype is not correlated with the age-dependent accumulation of AT8-labeled tau aggregates and the accompanying neuroinflammation. We hypothesize that the expression of P301L mutant tau disrupted the physiological functions of tau, resulting in the functional electrophysiological phenotype. Whether this functional effect drives neurodegeneration or is a separable phenomenon has implications for understanding the mechanisms underlying the role of tau variation in neurodegenerative conditions.