GABAergic Dysfunction in Alzheimer's Disease Models

Gamma-aminobutyric acid (GABA) mediates the principal inhibitory control of neuronal circuits, maintaining a precise excitatory/inhibitory (E/I) balance essential for learning, memory and emotional regulation. In experimental models of Alzheimer’s disease (AD), accumulation of β-amyloid and hyperphosphorylated tau disrupts GABAergic interneuron populations—particularly parvalbumin-expressing cells—and alters the distribution and function of GABA receptors. These perturbations contribute to network hyperexcitability, impaired synaptic plasticity and behavioural deficits including memory loss and anxiety. Both amyloid and tau pathologies have been shown to reduce inhibitory tone via loss of interneurons, down-regulation or mislocalisation of synaptic and extrasynaptic GABA receptors, and remodelling of perineuronal nets. Restoring GABAergic function in these models can normalise synaptic connectivity, ameliorate cognitive deficits and attenuate neuroinflammation, highlighting inhibitory circuits as a promising therapeutic target.

Research from Nature Portfolio

A foundational study explored combination therapy with licenced modulators of excitatory and inhibitory neurotransmission. By co-administering agents acting on GABA/glycine and glutamatergic pathways, researchers achieved synergistic neuroprotection of neuronal and cerebrovascular structures in vitro exposed to amyloid oligomers. In mouse models expressing familial AD mutations, this regimen restored synaptic protein profiles and alleviated spatial memory deficits, demonstrating that re-establishing E/I balance through repurposed drugs holds potential for AD intervention.

GABAergic Dysfunction in Alzheimer's Disease Models publication trend

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

Technical terms

GABAergic system: Network of neurons and receptors using gamma-aminobutyric acid to inhibit neuronal firing and regulate circuit excitability.

Parvalbumin-expressing interneurons: Fast-spiking inhibitory neurons critical for timing and synchrony of cortical and hippocampal networks.

δ-GABAA receptors: Extrasynaptic GABAA receptor subtypes containing the δ subunit, responsible for persistent tonic inhibition.

Perineuronal nets (PNNs): Extracellular matrix structures enveloping certain inhibitory neurons, modulating synaptic stability and receptor accessibility.

Excitatory/inhibitory (E/I) balance: Homeostatic equilibrium between excitatory glutamatergic and inhibitory GABAergic signalling necessary for normal brain function.

References

1. Decreased extrasynaptic δ‐GABAA receptors in PNN‐associated parvalbumin interneurons correlates with anxiety in APP and tau mouse models of Alzheimer's disease. British Journal of Pharmacology (2024).
2. Tau pathology induces loss of GABAergic interneurons leading to altered synaptic plasticity and behavioral impairments. Acta Neuropathologica Communications (2013).
3. Glutamate and GABA in Microglia-Neuron Cross-Talk in Alzheimer’s Disease. International Journal of Molecular Sciences (2021).
4. Impaired Expression of GABA Signaling Components in the Alzheimer’s Disease Middle Temporal Gyrus. International Journal of Molecular Sciences (2020).
5. Combining two repurposed drugs as a promising approach for Alzheimer's disease therapy. Scientific Reports (2015).