Perineuronal Net Receptor PTPσ Regulates Retention of Memories

Abstract

Perineuronal nets (PNNs) have an important physiological role in the 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 newly acquired skills and information. Modulation of PNN function by various techniques enhances plasticity and regulates the 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 (CSPGs) from PNNs] in retention of memories using Novel Object Recognition and Fear Conditioning 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 did not 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 amygdaloid complex of PTPσ^+/- mice, but other TRKB-mediated signaling pathways are not affected. Our data suggest that PTPσ downregulation promotes TRKB phosphorylation in different brain areas, improves short-term memory performance but disrupts long-term memory retention in the tested animal models. 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.

Keywords: BDNF; Ntrk2; PNNs; PTPRS; TrkB; memory; perineuronal nets; plasticity.

Figure 1

Molecular profile of changes in plasticity-related proteins induced by PTPσ genetic deficiency in different brain areas. (A) PTPσ^+/– mice have increased phosphorylation of TRKB receptors (pTRKB) and (B) no changes in total TRKB levels in the prefrontal cortex (PFC), hippocampus (HPC), and amygdala (AMG). PTPσ^+/– mice display (C) increased phosphorylation of PLCγ1 (pPLCγ1), no changes in phosphorylation of (D,E) Erk, (F) Akt, (G) p70S6 kinase and no changes in total levels of (H) PSD-93 and (I) PSD-95 expression. Data on (A) was measured by ELISA and on (B–I) by Western blot. Data were analyzed by two-way ANOVA *p < 0.05.

Figure 2

PTPσ^+/– mice demonstrate improved short-term but impaired long-term memory. PTPσ^+/– mice have (A) improved short-term memory and (B) impaired long-term memory and no changes in the total exploratory activity in the Novel Object Recognition test. (C) The fear response triggered by the cue in the retrieval session was potentiated by the context in WT but not in the PTPσ^+/– mice. Data were analyzed by (A,B) Mann–Whitney test, and (C) two-way ANOVA. *p < 0.05, **p < 0.01, ***p < 0.001. In (C): ^#p < 0.05 (vs. WT cue), *p < 0.05 (vs. WT context+cue).

Figure 3

PTPσ^+/– mice exhibit normal behavior in tests that do not involve cognitive flexibility. PTPσ^+/– mice display no behavioral changes in (A) elevated plus maze, (B) marble burying, (C) open field, and (D) forced swimming tests as compared to their wild-type littermates. Data were analyzed by t-test (A total time, C,D) or by Mann–Whitney test (A, # entries for Open and Closed Arms, and B).