Chondroitin 6-sulphate is required for neuroplasticity and memory in ageing

Abstract

Perineuronal nets (PNNs) are chondroitin sulphate proteoglycan-containing structures on the neuronal surface that have been implicated in the control of neuroplasticity and memory. Age-related reduction of chondroitin 6-sulphates (C6S) leads to PNNs becoming more inhibitory. Here, we investigated whether manipulation of the chondroitin sulphate (CS) composition of the PNNs could restore neuroplasticity and alleviate memory deficits in aged mice. We first confirmed that aged mice (20-months) showed memory and plasticity deficits. They were able to retain or regain their cognitive ability when CSs were digested or PNNs were attenuated. We then explored the role of C6S in memory and neuroplasticity. Transgenic deletion of chondroitin 6-sulfotransferase (chst3) led to a reduction of permissive C6S, simulating aged brains. These animals showed very early memory loss at 11 weeks old. Importantly, restoring C6S levels in aged animals rescued the memory deficits and restored cortical long-term potentiation, suggesting a strategy to improve age-related memory impairment.

Single‐Nucleus RNA Sequencing Reveals that Decorin Expression in the Amygdala Regulates Perineuronal Nets Expression and Fear Conditioning Response after Traumatic Brain Injury

“…What's more, Dcn specifically regulated PNNs surrounding excitatory neurons, which is unlike the functions of chABC and Chst3. [ 42 ]…”

“…What's more, Dcn specifically regulated PNNs surrounding excitatory neurons, which is unlike the functions of chABC and Chst3. [42] PNNs-mediated regulation of synaptic plasticity has been widely reported, [8] and the glutamate-GABA balance is very important for maintaining normal function in the BLA. [43] To inves-tigate whether the glutamate-GABA balance was changed in the groups, the expression levels of NR1, NR2, NR3, and Gad67 in the BLA were observed.…”

The “Loss” of Perineuronal Nets in Alzheimer's Disease: Missing or Hiding in Plain Sight?

“…These shifts in glycan-protein interactions are predicted to be driven primarily by changes in the PNN CS-GAG isomer composition, which consists of five differentially sulfated CS isomers in the human brain including non-sulfated [CS-O (0S)], mono-sulfated [CS-A (4S), CS-C (6S)] and di-sulfated [CS-D (2S6S), CS-E (4S6S)] variants ( Figure 3A ). The relative abundance of each CS isomer incorporated into the PNN matrix comprises a matrix “sulfation code” that links glycan-protein interactions with PNN biological functions including neuroplasticity and synaptic stability [CS-A (4S) and CS-C (6S) isomers (Miyata et al, 2012 ; Foscarin et al, 2017 ; Yang et al, 2021 )], diffusion [CS-O (0S) (Syková and Nicholson, 2008 )], neuroregeneration [CS-D (2S6S) (Shida et al, 2019 )], and neuroinflammation [CS-E (4S6S) (Gilbert et al, 2005 )]. We refer to recently published reviews that provide detailed and specific descriptions of glycan-protein binding interactions including that of CS-GAGs with extracellular growth factors, receptors, and guidance proteins (Djerbal et al, 2017 ; Vallet et al, 2021 ).…”

Changes in Brain Matrix Glycan Sulfation Associate With Reactive Gliosis and Motor Coordination in Mice With Head Trauma

“…In our model system, the cortex is mostly removed from this circuit, yet the thalamus remains intact (Figure 1A). Since 6S-CS sulfation is required for neuroplasticity and associated behavioral deficits in mice (Yang et al, 2021), we sought to determine whether the significant differences in thalamic 6S-CS abundance (Table 2) were associated with motor coordination defects in mice with CCI. As such, we correlated the latency to fall with the thalamic 6S-CS levels for naïve, 7 days post-sham, and 7 days post-CCI mice.…”