Plastic, Fantastic Brains: Study Identifies Crucial Compound That Supports Neuroplasticity and Memory in Mice

Life in plastic, it's fantastic — not only for Ken and Barbie but for our brains too...well, not that kind of plastic. Neuroplasticity, or the brain’s ability to adapt, change its structure, and rewire connections called synapses in response to new experiences, is a key player in maintaining cognitive vitality and memory with age. A more adaptable brain better repairs itself after damage or injury, driving researchers to zero in on the mechanisms behind neuroplasticity as a way to support cognition with age.

One such research team, based out of the Universities of Cambridge and Leeds in England, did just that. Published in Molecular Psychiatry in July 2021, Yang and colleagues successfully reversed age-related memory loss in a series of experiments with rodents. By targeting specific structures in the brain called perineuronal nets and boosting the activity of a compound called chondroitin-6-sulfate, this research sets the stage for testing similar interventions in humans. And, with that, potentially helping the ​​40% of people aged 65 or older who experience age-related memory impairment.  

Nothin’ But (Perineuronal) Nets

Perineuronal nets (PNNs) are cartilage-like structures in the extracellular matrix — a network of compounds that provides structural ‘scaffolding’ to the brain — that primarily surround inhibitory neurons and regulate levels of synaptic plasticity. These structures appear in the brain during early childhood when enhanced developmental plasticity tends to decline. With increasing age, PNNs ensure that plasticity is partially turned off, making the brain more efficient for use but less adaptable. 

The ability of PNNs to control plasticity depends on compounds called chondroitin sulfates, which are building blocks to cartilage. Chondroitin-4-sulfate (C4S) inhibits brain plasticity, while another form, chondroitin-6-sulfate (C6S), allows for increased synaptic adaptability. With age, the balance between these two tends to shift — increasing C4S activity while reducing C6S — which researchers believe leads to age-related memory impairment.  

Behavioral Tests Baffle Aged Animals

In this study, Yang and colleagues looked at how manipulating aged older rodents’ PNNs — by making them more C6S-dominant or deleting PNN activity altogether — affected cognition, using three tests of memory: spontaneous object recognition (SOR), spontaneous alternation (SA), and marble burying (MB). 

The SOR test measures spontaneous exploratory behavior, as young rodents tend to seek out novel items — meaning, they will prefer to explore the new over the familiar, demonstrating recognition for objects they’ve already seen. This test requires proper functioning of the brain’s perirhinal cortex (PRh), which plays an ​​important role in object recognition and storing object-related information memories. 

Similarly, the SA test assesses the willingness of rodents to explore new environments in a maze, relying on the hippocampus — the region of the brain most associated with learning and memory. The third test, marble burying, is a rodent-specific exploratory behavior task — simply burying exposed marbles — that requires proper functioning of the hippocampus, frontal cortex, and prefrontal cortex, which regulate attention, emotional and impulse control, and problem-solving.   

Unsurprisingly, the aged, 20-month-old mice (equivalent to the upper-60s in human years) exhibited diminished memory retention on all three tests, while young mice showed robust memory capabilities. The research team then wanted to know if PNNs were responsible for this age-related memory loss, which they accomplished by deleting a gene called hapln1 to diminish PNN activity entirely. 

They found that this attenuation of PNN activity prevented age-related memory loss in the aged mice on the SOR test, extending their memory retention from 6 hours to 48 hours after first seeing the novel objects. These results indicate that PNNs are implicated in the loss of SOR memory in aged mice.

Chondroitin-6-Sulfate Proves Crucial For Cognition

Next, Yang and colleagues genetically reduced C6S activity in the brains of aged mice, working with the theory that an unbalanced ratio of C4S to C6S inhibits neuroplasticity and worsens memory. They found that increasing this ratio by over 50% (to be more C4S-dominant) in mice as young as 11 weeks (early-20s in humans) strongly inhibited neurite outgrowth — ​​ the process of developing neurons producing new projections as they grow — and led to premature memory deficits on the SOR, SA, and MB tests. 

On the flip side, boosting C6S activity benefited memory and cognition, essentially reversing the age-related memory loss. Using a “viral vector” — a standard method for delivering genetic material to target cells — that contained a gene to restore C6S activity, the 20-month-old mice showed no memory deficit whatsoever, underlying the importance of C6S levels on memory and neuroplasticity. 

As one of the study’s authors, Dr. Jessica Kwok from the School of Biomedical Sciences at the University of Leeds, says of this experiment, "We saw remarkable results when we treated the ageing mice with this treatment. The memory and ability to learn were restored to levels they would not have seen since they were much younger."

From Mice to Men

The authors of this study are hopeful that manipulating chondroitin sulfate and PNN activity will prove beneficial to supporting human cognition, stating, “Overall the results of this study demonstrate a mechanism for the loss of memory in the aged brain and indicate that treatments targeting PNNs have the potential to ameliorate memory deficits associated with ageing.” 

This research could have potentially wide-reaching impacts, as reducing PNN activity, or shifting the balance towards increased chondroitin-6-sulfate activity, proved to be so beneficial to the aged rodents’ brains. The research team has already identified a possible intervention for humans that inhibits PNN formation — but it’s far too soon to tell whether or not this will support memory or cognition in aging humans. 

However, senior author, Professor James Fawcett from the University of Cambridge, concludes optimistically, "What is exciting about this is that although our study was only in mice, the same mechanism should operate in humans — the molecules and structures in the human brain are the same as those in rodents. This suggests that it may be possible to prevent humans from developing memory loss in old age."

References: 

Yang, S., Gigout, S., Molinaro, A. et al. Chondroitin 6-sulphate is required for neuroplasticity and memory in ageing. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01208-9