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 PTP{sigma} (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 (PTP{sigma}+/-), 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, PTP{sigma}+/- mice didnt 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 PTP{sigma} 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 PLC{gamma} are increased in the hippocampus, prefrontal cortex and amygdala of PTP{sigma}+/- mice, but other TRKB-mediated signaling pathways are not affected. Our data suggest that disruption of PNN-PTP{sigma} complex facilitates short-term memory by promoting TRKB phosphorylation in different brain areas, but that PTP{sigma} activity is required for the retention of long-term memories. Inhibition of PTP{sigma} or disruption of PNN-PTP{sigma}-TRKB complex might be a potential target for disorders where negative modulation of the acquired memories can be beneficial. Conflict of interestThe authors declare no conflict of interest. FundingThis work was supported by Doctoral Program in Integrative Life Science, Jalmari ja Rauha Ahokkaan Saatio grant, Centre for International Mobility (CIMO) Grant TM-16-10112, and by grants from European Research Council (#322742), EU Joint Programme - Neurodegenerative Disease Research (JPND) CircProt (#301225 and #643417), Sigrid Juselius Foundation, Jane and Aatos Erkko Foundation, and the Academy of Finland (#294710 and #307416). None of the funders had a role in the data acquisition, analysis or manuscript preparation. Author contributionsPC, CB and EC designed the study; AL, PC and CB performed the experiments and analyzed the data; AL wrote the manuscript draft; AL, PC, CB and EC revised the manuscript. Contribution to the Field StatementPlasticity of neuronal networks increases brains ability to adapt and it is compromised in various conditions including psychiatric diseases, brain injuries, neurodevelopmental and neurodegenerative disorders. Perineuronal nets, through their receptor PTP{sigma} restrict neuronal plasticity in adult brain, which is considered important for the retention of long-term memories. We have previously shown that this restricted plasticity is mediated by inhibition by PTP{sigma} of the TRKB neurotrophin receptor. We have now investigated the biochemical and behavioral phenotype of mice with reduced PTP{sigma} expression. We observed that PTP{sigma}+/- mice have increased phosphorylation of TRKB and its downstream partner PLC{gamma}1 in the prefrontal cortex, hippocampus and amygdala, demonstrating chronic overactivation of plasticity-related pathways. Consistently, PTP{sigma}+/- mice demonstrated facilitated learning but impaired long-term memory retention. Unexpectedly, long-term memory of PTP{sigma}+/- mice was impaired, suggesting that perneuronal net-stimulated PTP{sigma} activity is important in memory retention. This effect of neuronal "hyperplasticity" induced by PTP{sigma} knockout may be both beneficial and harmful in the treatment of human patients, which should be taken into account when developing therapeutic strategies.