Neuronal Hyperactivity in Alzheimer's Disease Models

Neuronal hyperactivity emerges as an early and pervasive feature in experimental models of Alzheimer’s disease, manifesting before overt plaque deposition and memory impairment. Electrophysiological recordings in transgenic mice reveal aberrant synchronised discharges, interictal-like spikes and elevated network excitability predominantly in hippocampal and cortical circuits. This dysfunction reflects a disturbance in the excitatory/inhibitory balance, driven by altered intrinsic properties of pyramidal cells, impaired inhibitory interneuron function and pathological influences of amyloid-β and tau. Hyperactive networks contribute to accelerated amyloid accumulation, synaptic loss and cognitive deficits, while interventions that restore inhibitory tone or modulate specific ion channels can normalise oscillatory activity and ameliorate behavioural outcomes. These findings position network hyperexcitability both as a mechanistic contributor to disease progression and as a potential biomarker and therapeutic target across preclinical models.

Research from Nature Portfolio

Investigations using post-mortem human tissue have provided direct evidence of a pro-excitatory synaptic perturbation in Alzheimer’s disease. In parietal cortex samples from individuals with early-onset disease, anatomical and functional assays demonstrated an elevated excitatory-to-inhibitory synaptic ratio, implicating an intrinsic shift towards hyperexcitability within a key node of the default mode network. Complementary gene expression analyses confirmed upregulation of excitatory markers relative to inhibitory components. In a widely used murine model of amyloidosis, early interictal spikes emerged during rapid-eye movement sleep long before amyloid deposition or behavioural decline. These synchronised potentials, resembling epileptiform discharges, suggest that hyperexcitability is both an early biomarker and a circuit-level event that may precipitate later pathology.

Neuronal Hyperactivity in Alzheimer's Disease Models publication trend

The graph below shows the total number of articles in neuronal hyperactivity in alzheimer's disease models across all publications each year (not limited to Nature Index journals).

Technical terms

Neuronal hyperexcitability: An increased propensity of neurons to fire action potentials, often leading to synchronised discharges and network instability.

Excitatory/inhibitory (E/I) balance: The dynamic equilibrium between excitatory synaptic inputs (primarily glutamatergic) and inhibitory inputs (primarily GABAergic) that regulates neuronal firing and network rhythms.

Parvalbumin interneurons: A class of fast-spiking inhibitory GABAergic cells critical for timing and synchronisation of neural circuits, particularly gamma oscillations.

Gamma oscillations: High-frequency (20–80 Hz) network rhythms implicated in cognitive processes, whose disruption reflects altered synchrony in disease states.

References

1. Targeting galectin-3 to counteract spike-phase uncoupling of fast-spiking interneurons to gamma oscillations in Alzheimer’s disease. Translational Neurodegeneration (2023).
2. Early restoration of parvalbumin interneuron activity prevents memory loss and network hyperexcitability in a mouse model of Alzheimer’s disease. Molecular Psychiatry (2019).
3. Neuronal hyperexcitability in Alzheimer’s disease: what are the drivers behind this aberrant phenotype?. Translational Psychiatry (2022).
4. Interictal spikes during sleep are an early defect in the Tg2576 mouse model of β-amyloid neuropathology. Scientific Reports (2016).
5. Increased excitatory to inhibitory synaptic ratio in parietal cortex samples from individuals with Alzheimer’s disease. Nature Communications (2021).