Perineuronal net receptor PTPσ regulates retention of memories

Abstract

Perineuronal nets (PNNs) have an important physiological role in retention of learning by restricting cognitive flexibility. Their deposition peaks after developmental periods of intensive learning, usually in late childhood, and they help in long-term preservation of new acquired skills and information. Modulation of PNN function by various techniques enhances plasticity and regulates retention of memories, which may be beneficial when memory persistence entails negative symptoms such as post-traumatic stress disorder (PTSD). In this study, we investigated the role of PTPσ (receptor-type tyrosine-protein phosphatase S, a phosphatase that is activated by binding of chondroitin sulfate proteoglycans from PNNs) in retention of memories using novel object recognition and fear conditioning rodent models. We observed that mice haploinsufficient for PTPRS gene (PTPσ+/-), although having improved short-term object recognition memory, display impaired long-term memory in both novel object recognition and fear conditioning paradigm, as compared to WT littermates. However, PTPσ+/- mice didn't show any differences in behavioral tests that do not heavily rely on cognitive flexibility, such as elevated plus maze, open field, marble burying and forced swimming test. Since PTPσ has been shown to interact with and dephosphorylate TRKB, we investigated activation of this receptor and its downstream pathways in limbic areas known to be associated with memory. We found that phosphorylation of TRKB and PLCγ are increased in the hippocampus, prefrontal cortex and amygdala of PTPσ+/- mice, but other TRKB-mediated signaling pathways are not affected. Our data suggest that disruption of PNN-PTPσ complex facilitates short-term memory by promoting TRKB phosphorylation in different brain areas, but that PTPσ activity is required for the retention of long-term memories. Inhibition of PTPσ or disruption of PNN-PTPσ-TRKB complex might be a potential target for disorders where negative modulation of the acquired memories can be beneficial.

New insights into glial scar formation after spinal cord injury

“…Perhaps through dampening autophagic flux (Tran et al 2020), CSPGs through protein tyrosine phosphatase receptor sigma (PTPRσ) binding promote initial adhesion and receptor recruitment necessary for synaptogenesis (Han et al 2016;Bomkamp et al 2019). It has recently been found that the PNN-PTPRσ complex exerts its inhibitory action on neuronal plasticity, at least in part, by restricting signaling of the neurotrophic receptor tyrosine kinase 2 (TRKB) (Lesnikova et al 2021).…”

Activation of TrkB in Parvalbumin interneurons is required for the promotion of reversal learning in spatial and fear memory by antidepressants

“…The TRAP analysis also points towards the regulation of PNN s as the target of fluoxetine action. We have previously shown that plasticity promoted by the reduction of PNN s by chondroitinase treatment is also dependent on the expression of TrkB in PV interneurons and that this effect is mediated by the inhibition of the PNN receptor, receptor-type tyrosine-protein phosphatase Sigma (PTPRS) [39]. In addition, fluoxetine was shown to disrupt the interaction between TrkB and PTPRS, functionally mimicking the effects of PNN disruption [39].…”

“…We have previously shown that plasticity promoted by the reduction of PNN s by chondroitinase treatment is also dependent on the expression of TrkB in PV interneurons and that this effect is mediated by the inhibition of the PNN receptor, receptor-type tyrosine-protein phosphatase Sigma (PTPRS) [39]. In addition, fluoxetine was shown to disrupt the interaction between TrkB and PTPRS, functionally mimicking the effects of PNN disruption [39]. Furthermore, it appears that fluoxetine specifically targets PV + interneurons which was also observed in visual cortex plasticity [16].…”