Metformin improves age-related visual cortex dysfunction in mice by reducing noise correlation in the primary visual cortex

Xiaoming Liu^1,2Yifeng Zhou^1,2*Jiachen Liu^3*Guangwei Xu^1,2*

• ¹Key Laboratory of Brain Function and Diseases, School of Life Science, USTC Life Sciences and Medicine, Hefei, Anhui Province, China
• ²University of Science and Technology of China, Hefei, China
• ³Anhui Medical College, Hefei, China, China

The age-related decline in visual processing is characterized by reduced orientation selectivity and a decreased signal-to-noise ratio in the primary visual cortex (V1). An elevated noise correlation, which reflects the shared variability between neurons, has been observed in aging brains and may contribute to impaired visual processing. Metformin has neuroprotective effects against various age-related disorders; however, its potential role in preserving visual function remains unclear. Here, we investigated whether 3 weeks of acute gavage with metformin improves visual processing in 12-month-old mice compared to 8-week-old mice by modulating neural noise in the V1. In vivo electrophysiological recordings revealed that aging led to V1 neuronal hyperactivity, accompanied by reduced orientation selectivity, a decreased signal-to-noise ratio, and increased response variability. Notably, aged mice exhibited increased noise correlation, response covariance, and population variability. Analysis of fast-spiking interneurons revealed impaired noise suppression in the inhibitory circuits of aged mice. Daily metformin treatment reversed these age-related alterations by improving fast-spiking neuron-mediated decorrelation and reducing noise correlation. Mechanistically, metformin upregulated the protein expression levels of glutamic acid decarboxylase 67 and gephyrin, key components of inhibitory synapses, suggesting that metformin enhances visual processing by strengthening inhibitory signaling and reducing the correlated variability in the V1. Our findings identified metformin as a potential therapeutic strategy for age-related visual decline through the modulation of neural noise and inhibitory function.