Abstract
Alzheimer’s disease (AD) is characterized by neuronal loss and impaired synaptic transmission, ultimately leading to cognitive deficits. Early in the disease, the olfactory track seems most sensitive to tauopathy, while most plasticity studies focused on the hippocampal circuits. Functional network connectivity (FC) and long-term potentiation (LTP), considered as the plasticity substrate of learning and memory, were longitudinally assessed in mice of the P301S model of tauopathy following the course (time and location) of progressively neurodegenerative pathology (i.e., at 3, 6, and 9 months of age) and in their wild type (WT) littermates. Using in vivo local field potential (LFP) recordings, early (at three months) dampening in the gamma oscillatory activity and impairments in the phase-amplitude theta-gamma coupling (PAC) were found in the olfactory bulb (OB) circuit of P301S mice, which were maintained through the whole course of pathology development. In contrast, LFP oscillatory activity and PAC indices were normal in the entorhinal cortex, hippocampal CA1 and CA3 nuclei. Field excitatory postsynaptic potential (fEPSP) recordings from the Shaffer collateral (SC)-CA1 hippocampal stratum pyramidal revealed a significant altered synaptic LTP response to high-frequency stimulation (HFS): at three months of age, no significant difference between genotypes was found in basal synaptic activity, while signs of a deficit in short term plasticity were revealed by alterations in the fEPSPs. At six months of age, a slight deviance was found in basal synaptic activity and significant differences were observed in the LTP response. The alterations in network oscillations at the OB level and impairments in the functioning of the SC-CA1 pyramidal synapses strongly suggest that the progression of tau pathology elicited a brain area, activity-dependent disturbance in functional synaptic transmission. These findings point to early major alterations of neuronal activity in the OB circuit prior to the disturbance of hippocampal synaptic plasticity, possibly involving tauopathy in the anomalous FC. Further research should determine whether those early deficits in the OB network oscillations and FC are possible mechanisms that potentially promote the emergence of hippocampal synaptic impairments during the progression of tauopathy.
Highlights
Neurodegenerative diseases such as Alzheimer’s disease (AD) are characterized by gradual and irrevocable damage to neural networks, leading to a progressive decline of neural plasticity and to dramatic cognitive deficits
At recording months six and nine, this reduction in the high gamma oscillations was maintained at the olfactory bulb (OB) network (p < 0.01, two-sample t-test) (Figure 1, second and third left panels)
No overt effect on network gamma activity was found in frontal, entorhinal cortex (EC), or the hippocampal recording sites (Figure 1, first to third middle and right panels)
Summary
Neurodegenerative diseases such as Alzheimer’s disease (AD) are characterized by gradual and irrevocable damage to neural networks, leading to a progressive decline of neural plasticity and to dramatic cognitive deficits. Tau proteins are referred to as either p-tau, which indicates hyperphosphorylated tau proteins correlated with the formation of neurofibrillary tangles in AD patients’ brains [3,4], or t-tau, which consists of different tau isomers correlated with the severity of neurodegeneration and neuronal or axonal damage [5,6]. These biomarkers are not widely used in clinical settings, due to either the invasiveness of the procedures and/or costs involved [1,7]. Robust functional index, which could be used for an accurate, inexpensive, and non-invasive diagnosis is crucial
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