Synaptic dysfunction and disconnectivity are core deficits in Alzheimer’s disease (AD), preceding clear changes in histopathology and cognitive functioning. Here, the early and late effects of tau pathology induction on functional network connectivity were investigated in P301L mice. Multichannel EEG oscillations were used to compute (1) coherent activity between the prefrontal cortex (PFC) and hippocampus (HPC) CA1-CA3 networks; (2) phase-amplitude cross frequency coupling (PAC) between theta and gamma oscillations, which is instrumental in adequate cognitive functioning; (3) information processing as assessed by auditory evoked potentials and oscillations in the passive oddball mismatch negativity-like (MMN) paradigm. At the end, the density of tau aggregation and GABA parvalbumin (PV+) interneurons were quantified by immunohistochemistry. Early weakening of EEG theta oscillations and coherent activity were revealed between the PFC and HPC CA1 and drastic impairments in theta–gamma oscillations PAC from week 2 onwards, while PV+ interneurons count was not altered. Moreover, the tau pathology disrupted the MMN complex amplitude and evoked gamma oscillations to standard and deviant stimuli suggesting altered memory formation and recall. The induction of intracellular tau aggregation by tau seed injection results in early altered connectivity and strong theta–gamma oscillations uncoupling, which may be exploited as an early electrophysiological signature of dysfunctional neuronal networks.

Recently, the N-methyl-d-aspartate-receptor (NMDAR) antagonist ketamine has emerged as a fast-onset mechanism to achieve antidepressant activity, whereas its psychomimetic, dissociative and amnestic effects have been well documented to pharmacologically model schizophrenia features in rodents. Sleep–wake architecture, neuronal oscillations and network connectivity are key mechanisms supporting brain plasticity and cognition, which are disrupted in mood disorders such as depression and schizophrenia. In rats, we investigated the dynamic effects of acute and chronic subcutaneous administration of ketamine (2.5, 5 and 10 mg kg−1) on sleep–wake cycle, multichannels network interactions assessed by coherence and phase–amplitude cross-frequency coupling, locomotor activity (LMA), cognitive information processing as reflected by the mismatch negativity-like (MMN) component of event-related brain potentials (ERPs). Acute ketamine elicited a short, lasting inhibition of rapid eye movement (REM) sleep, increased coherence in higher gamma frequency oscillations independent of LMA, altered theta-gamma phase–amplitude coupling, increased MMN peak-amplitude response and evoked higher gamma oscillations. In contrast, chronic ketamine reduced large-scale communication among cortical regions by decreasing oscillations and coherent activity in the gamma frequency range, shifted networks activity towards slow alpha rhythm, decreased MMN peak response and enhanced aberrant higher gamma neuronal network oscillations. Altogether, our data show that acute and chronic ketamine elicited differential changes in network connectivity, ERPs and event-related oscillations (EROs), supporting possible underlying alterations in NMDAR–GABAergic signaling. The findings underscore the relevance of intermittent dosing of ketamine to accurately maintain the functional integrity of neuronal networks for long-term plastic changes and therapeutic effect.

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