Neural Excitatory/Inhibitory Imbalance in Motor Aging: From Genetic Mechanisms to Therapeutic Challenges

Abstract

Neural excitatory/inhibitory (E/I) imbalance plays a pivotal role in the aging process. However, despite its significant impact, the role of E/I imbalance in motor dysfunction and neurodegenerative diseases has not received sufficient attention. This review explores the mechanisms underlying motor aging through the lens of E/I balance, emphasizing genetic and molecular factors that contribute to this imbalance (such as SCN2A, CACNA1C, GABRB3, GRIN2A, SYT, BDNF…). Key regulatory genes, including REST, vps-34, and STXBP1, are examined for their roles in modulating synaptic activity and neuronal function during aging. With insights drawn from ALS, we discuss how disruptions in E/I balance contribute to the pathophysiology of age-related motor dysfunction. The genes discussed above exhibit a certain association with age-related motor neuron diseases (like ALS), a relationship that had not been previously recognized. Innovative genetic therapies, such as gene editing technology and optogenetic manipulation, are emerging as promising tools for restoring E/I balance, offering hope for ameliorating motor deficits in aging. This review explores the potential of these technologies to intervene in aging-related motor diseases, despite challenges in their direct application to human conditions.

Keywords

• E/I balance
• motor aging
• ALS
• genetic therapy
• excitatory toxicity
• inhibitory interneurons