Turecek, R. | bioRxiv Science

bioRxiv2026

Chondroitin 4-sulphate depletion enhances synaptic plasticity and memory in aging

Perineuronal nets (PNNs), specialised extracellular matrix structures enriched in chondroitin sulphate proteoglycans (CSPGs), are key regulators of synaptic plasticity, learning, and memory. Aging is characterised by a shift in chondroitin sulphate composition toward increased chondroitin-4-sulfation (C4S) and reduced C6S, a pattern associated with declining cognitive flexibility. Here, we investigated how selective reduction of C4S affects PNN structure, PV-interneuron connectivity, and cognitive performance across the lifespan. Conditional deletion of the C4-sulfotransferase Chst11 markedly reduced C4S levels and diminished dendritic PNN complexity while preserving somatic PNN structure. This partial destabilisation of PNNs increased excitatory synaptic input onto PV interneurons in both young and aged mice, without major alterations in basal hippocampal transmission or long-term potentiation. Behaviourally, Chst11 knockout mice showed robust and persistent protection against age-related cognitive decline. Working memory performance remained stable across aging, short-term spatial memory was enhanced from early adulthood onward, and object recognition memory was significantly prolonged at all retention delays, even in old age. Sociability and social novelty preference were also preserved longer in aging knockouts compared with controls. These improvements occurred despite an overall preservation of PNN architecture, indicating that modifying sulphation rather than removing CSPGs is sufficient to enhance plasticity. Our findings demonstrate that reducing C4S through Chst11 deletion confers long-lasting enhancements in cognitive function and mitigates aging-related decline. Targeting CS-GAG sulphation patterns may therefore represent a promising strategy for maintaining cognitive resilience and restoring plasticity in aging or neurodegenerative conditions.

neuroscience↗

bioRxiv2023

Hyperactive PI3Kinase delta enables long distance regeneration of the rat corticospinal tract

Maturation of central nervous system neurons leads to loss of their intrinsic regeneration potential. In particular after injury of the adult spinal cord there is minimal regeneration of corticospinal axons, which control gait and fine movement. Previous work has shown that knockdown of PTEN to increase PIP3 levels can promote regeneration in young animals, but the effect is much less in adults probably due to low PIP3 production. Here, we have transduced sensorimotor cortex neurons with a hyperactive form of PI3K, PI3K{delta}, which increases PIP3 in mature neurons. This enables cortical neurons to regenerate corticospinal axons and improve behavioural outcomes. We used a C4 dorsal column lesion model in adult rats and injected the right motor cortex at 4 sites concurrently with a mixture AAV1-PIK3CD and AAV1-eGFP or titre matched AAV1-eGFP only. We allowed rats to survive for 6, 9, 12 or 16 weeks. Immunostaining showed 70 - 80% co-expression in cortical neurons which remained stable at both 12 and 16 weeks. We counted GFP labelled axons in 20 m spinal cord sections. In PI3KCD-treated animals many axons were seen to have regenerated around the margins of lesions, collecting into a knot of axons with the typical appearance of regeneration at the caudal end. Tracing down the cord, and excluding axons and neurites that could have come from unlesioned ventral CST, we found axons extending up to 1 cm below lesions, numbers decreasing with distance from the lesion. After 16 weeks there were circa 200 axons at the caudal end of lesions with a regeneration index of 0.2, with half this number at 12 weeks. Behavioural testing for 16 weeks revealed functional improvements in skilled paw reaching, grip strength and ladder rung walking in rats treated with PIK3CD compared to GFP only controls. In addition to behavioural testing, functional recovery of PIK3CD treated rats was confirmed with electrophysiological recordings during which we stimulated the right pyramid. Cord dorsum potentials (CDPs) above and below lesion and EMG forepaw distal flexor muscles showed greatly increased connectivity compared with GFP only controls, lesion only controls and uninjured shams. We conclude that forcing upregulation of PI3K{delta} in cortical neurons leads to robust regeneration after spinal cord injury that results in functional restoration.

neuroscience↗