Inhibitory and Excitatory Imbalance in Neurodegenerative Diseases

Abstract

The delicate balance between excitatory and inhibitory (E/I) neurotransmission underpins normal brain function, maintaining neural network stability while allowing adaptive plasticity. Disruption of this equilibrium is increasingly recognized as a key pathogenic mechanism in a wide spectrum of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Aberrant shifts in the E/I ratio—manifesting as cortical hyperexcitability, impaired inhibitory tone, or maladaptive oscillations—can accelerate neuronal loss, impair cognition and motor control, and exacerbate disease progression. This review synthesizes current understanding of the molecular, cellular, and systems-level mechanisms leading to E/I imbalance in these conditions. It covers alterations in neurotransmitter systems, ion channel function, synaptic plasticity, and glial contributions, while integrating insights from neuroimaging, electrophysiology, and translational models. We further discuss emerging therapeutic strategies aimed at restoring E/I homeostasis and highlight the potential of E/I metrics as biomarkers for early detection and disease monitoring. Understanding these dynamics offers novel avenues for intervention and holds promise for slowing neurodegeneration.