Pathological Tau Disrupts Ongoing Network Activity

Abstract

Pathological tau leads to dementia and neurodegeneration in tauopathies, including Alzheimer's disease. It has been shown to disrupt cellular and synaptic functions, yet its effects on the function of the intact neocortical network remain unknown. Using in vivo intracellular and extracellular recordings, we measured ongoing activity of neocortical pyramidal cells during various arousal states in the rTg4510 mouse model of tauopathy, prior to significant cell death, when only a fraction of the neurons show pathological tau. In transgenic mice, membrane potential oscillations are slower during slow-wave sleep and under anesthesia. Intracellular recordings revealed that these changes are due to longer Down states and state transitions of membrane potentials. Firing rates of transgenic neurons are reduced, and firing patterns within Up states are altered, with longer latencies and inter-spike intervals. By changing the activity patterns of a subpopulation of affected neurons, pathological tau reduces the activity of the neocortical network.

Adenosine A 1 receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280

“…****P < 0.0001 (two-way ANOVA with Tukey's test). (15). The reduced ATP levels, dendritic spine loss, diminished neuronal activity, and impaired presynaptic functioning are reminiscent of adenosine A 1 receptor signaling.…”

“…Hypometabolism (i.e., diminished neuronal activity) is strongly associated with neurodegeneration (12)(13)(14). Moreover, pathological Tau can disrupt ongoing network activity even at early asymptomatic stages (15). The relationship between hypometabolism seen in human tauopathies, Tau aggregation, and its effect on neuronal activity is not well established.…”

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…Aβ can control synaptic activity, depress excitatory transmission at the synaptic level, while triggering aberrant patterns of neuronal circuit activity and epileptiform discharges at the network level (Palop & Mucke, 2010). Using a tauopathy mouse model with in vivo intracellular and extracellular recordings, pathological tau was found to alter neocortical neuronal oscillatory patterns and firing patterns (Menkes‐Caspi et al, 2015). …”

Tau neurotoxicity and rescue in animal models of human Tauopathies

“…In vivo recordings in mice expressing mutant Tau (rTg4510, mutation P301L) displayed a disrupted spontaneous activity and reduced firing rates of neocortical neurons [40]. Another line expressing aggregation-prone Tau (mutation DK280) alters presynaptic morphology (e.g.…”