New research published in journal neurobiology of disease found that excessive inhibitory connectivity in key brain regions is associated with age-related declines in memory and cognition, and that artificially recreating this imbalance in young animals produced the same deficits.
The brain functions through a careful balance of two opposing forces: excitatory signals that activate neurons (brain cells), and inhibitory signals that dampen neuron (brain cell) activity. The prefrontal cortex, the region at the front of the brain responsible for complex thinking, planning, and memory, is known to be susceptible to the effects of aging. Previous studies suggested that the ratio of inhibitory to excitatory activity in this region may become imbalanced with age, but a direct causal relationship remained unclear.
With that in mind, researchers set out to see whether excessive inhibitory activity in the prefrontal cortex is not only associated with, but actually causes, cognitive decline with aging.
A research team led by Iason Keramidis from Université Laval in Canada tested 43 older male mice (roughly equivalent to older humans) and 17 young adult male mice on a series of cognitive tasks assessing memory, exploration of new environments, and social behavior.
Using an advanced statistical approach that combines multiple rounds of clustering analysis and techniques to visualize similarities in behavioral patterns, the researchers were able to identify two stable subgroups within the older animals. The first was a “cognitively sensitive” group of 26 mice that displayed significant memory and exploratory deficits (and increased anxiety-like behavior) while maintaining normal social preferences. The second group, a “resilient” group of 17 mice, showed some deficits in social interaction but relatively preserved memory and exploratory abilities.
When the researchers examined brain tissue from each group, they found that the more susceptible mice had higher levels of gephyrin and VGAT, two proteins involved in inhibitory connections, particularly in the prefrontal cortex. Importantly, proteins associated with excitatory binding were unchanged, suggesting that this change is selective rather than a sign of widespread degradation.
Further microscopic imaging revealed that susceptible mice did not simply have more protein packed into existing synapses, but actually had a higher density of inhibitory synapses (connections) in their prefrontal cortex. This indicates structural, long-term changes in brain circuitry, rather than temporary fluctuations in brain activity.
To test whether this excessive suppression could directly cause cognitive problems, the researchers used a technique called optogenetics. This technique uses light to precisely turn specific types of neurons on or off. When they activated inhibitory neurons in the prefrontal cortex of young, healthy mice, they immediately showed the same memory deficits, reduced exploratory abilities, and anxiety-like behaviors seen in susceptible older mice. Importantly, when the same stimulus was given to older, cognitively impaired mice, no further effects occurred. This is consistent with the idea that the inhibitory systems of these animals are already operating at their maximum limits.
As the authors point out, this “convergence of a sustained structural increase in the number of inhibitory synapses and a rapid optogenetic rise in inhibitory tone supports a model in which susceptible aging is characterized by a chronic increase in inhibitory synaptic load within prefrontal circuits, which is sufficient to cause cognitive impairment.”
The researchers highlight that these findings may complicate future treatments for age-related cognitive decline. For example, in Alzheimer’s disease, the brain is often inhibited “too little,” leading to hyperactivity of brain cells. When doctors give older patients drugs designed to increase inhibition to treat Alzheimer’s disease, they may inadvertently exacerbate the normal age-related cognitive decline caused by excessive inhibition found in this study.
The study is not without limitations. For example, optogenetic manipulation artificially increases inhibition rapidly, whereas real aging involves slow and complex changes across brain networks. The study also used only male mice, so the results may not fully apply to female mice (or humans), as the effects of hormones on brain plasticity vary. Additionally, some of the social behavior results are complicated by location preferences within the test apparatus, making clean interpretation of these particular results difficult.
The study, “Excessive suppression of the medial prefrontal cortex contributes to cognitive susceptibility in aging,” was authored by Iason Keramidis, Patrick Desrosiers, Andrée-Anne Verreault, Romain Sansonetti, Reza Hazrati, Antoine G. Godin, and Yves De Koninck.
