Chondroitinase and Antidepressants Promote Plasticity by Releasing TRKB from Dephosphorylating Control of PTPσ in Parvalbumin Neurons

Abstract

Perineuronal nets (PNNs) are an extracellular matrix structure rich in chondroitin sulfate proteoglycans (CSPGs), which preferentially encase parvalbumin-containing (PV⁺) interneurons. PNNs restrict cortical network plasticity but the molecular mechanisms involved are unclear. We found that reactivation of ocular dominance plasticity in the adult visual cortex induced by chondroitinase ABC (chABC)-mediated PNN removal requires intact signaling by the neurotrophin receptor TRKB in PV⁺ neurons. Additionally, we demonstrate that chABC increases TRKB phosphorylation (pTRKB), while PNN component aggrecan attenuates brain-derived neurotrophic factor (BDNF)-induced pTRKB in cortical neurons in culture. We further found that protein tyrosine phosphatase σ (PTPσ, PTPRS), receptor for CSPGs, interacts with TRKB and restricts TRKB phosphorylation. PTPσ deletion increases phosphorylation of TRKB in vitro and in vivo in male and female mice, and juvenile-like plasticity is retained in the visual cortex of adult PTPσ-deficient mice (PTPσ^+/-). The antidepressant drug fluoxetine, which is known to promote TRKB phosphorylation and reopen critical period-like plasticity in the adult brain, disrupts the interaction between TRKB and PTPσ by binding to the transmembrane domain of TRKB. We propose that both chABC and fluoxetine reopen critical period-like plasticity in the adult visual cortex by promoting TRKB signaling in PV⁺ neurons through inhibition of TRKB dephosphorylation by the PTPσ-CSPG complex.SIGNIFICANCE STATEMENT Critical period-like plasticity can be reactivated in the adult visual cortex through disruption of perineuronal nets (PNNs) by chondroitinase treatment, or by chronic antidepressant treatment. We now show that the effects of both chondroitinase and fluoxetine are mediated by the neurotrophin receptor TRKB in parvalbumin-containing (PV⁺) interneurons. We found that chondroitinase-induced visual cortical plasticity is dependent on TRKB in PV⁺ neurons. Protein tyrosine phosphatase σ (PTPσ, PTPRS), a receptor for PNNs, interacts with TRKB and inhibits its phosphorylation, and chondroitinase treatment or deletion of PTPσ increases TRKB phosphorylation. Antidepressant fluoxetine disrupts the interaction between TRKB and PTPσ, thereby increasing TRKB phosphorylation. Thus, juvenile-like plasticity induced by both chondroitinase and antidepressant treatment is mediated by TRKB activation in PV⁺ interneurons.

Keywords: BDNF; CSPG; PTPRS; RPTPσ; chABC; perineuronal nets.

Figure 1.

ChABC-induced plasticity requires intact TRKB signaling in PV⁺ neurons. A, PNN removal by local chABC injection reopens critical period-like plasticity in the visual cortex of WT but not in mice heterozygous for TRKB deletion in PV interneurons (PV-TRKB^+/−), as measured by optical imaging of the intrinsic signal before (IOS1) and after 7 d of MD (IOS2). ODI: ocular dominance index. B, ChABC treatment (30 min) of cortical neurons (7 DIV) increases pTRKB. C, The CSPG aggrecan, added to cortical neurons (6 DIV) for 24 h, attenuates BDNF-induce pTRKB in cortical neurons. Columns and bars represent mean ± SEM, respectively, and scattered points represent individual values. Data were analyzed by three-way ANOVA and Tukeys's post hoc (A), Mann–Whitney (B), or two-way ANOVA followed by Tukey's multiple comparison test (C); *p < 0.05, **p < 0.005, ***p < 0.0005.

Figure 2.

Deletion of CSPG receptor PTPσ facilitates pTRKB and delays closure of the critical period in the visual cortex of adult mice. A, PTPσ can be immunoprecipitated with anti-TRKB antibody in samples from a TRKB-expressing, but not from a TRKA-expressing, cell line. B, Interaction of TRKB and PTPσ is reduced in embryonic cortical cultures from PTPσ^+/− mice when compared with those from WT mice. C, pTRKB is increased in cortical cultures from PTPσ^+/− and PTPσ^−/− mice. D, Adult PTPσ^+/− mice have increased pTRKB and (E) a slight decrease in total TRKB levels in the visual cortex. F, Critical period-like plasticity is present in the visual cortex of two-month-old PTPσ^+/− mice (red circles) but not in WT littermates (black squares), as measured by optical imaging of the intrinsic signal before (IOS1) and after 3.5 d of MD (IOS2). ODI: ocular dominance index. Columns and bars represent mean ± SEM, respectively, and scattered points represent individual values. Data were analyzed by two-way (F) or one-way ANOVA (C) followed by Bonferroni's or Tukey's post hoc, respectively; unpaired t test (B) or Mann–Whitney test (D, E); *p < 0.05, **p < 0.005, ***p < 0.0005.

Figure 3.

Fluoxetine disrupts TRKB and PTPσ interaction in vitro and in vivo. A, Fluoxetine (FLX) disrupts the interaction between TRKB and PTPσ in 7 DIV cortical neurons, and (B) in the visual cortex (V1) of mice systemically treated (30 mg/kg, i.p.) 30 min before tissue dissection. C, Fluoxetine does not affect the detection of PTPσ extracellular domain on the cell surface, indicating no effect on PTPσ surface exposure or PTPσ ectodomain shedding. D, Mutation of the TRKB transmembrane domain (R427A/Y433F) partially disrupts the TRKB:PTPσ interaction and abolishes the effects of fluoxetine on it. Columns and bars represent mean ± SEM, respectively. Data were analyzed by one-way ANOVA followed by Bonferroni's (A), two-way ANOVA (D), or unpaired t test (B, C); *p < 0.05, **p < 0.005.

Figure 4.

Schematic model of how chondroitinase and antidepressant treatments promote plasticity by releasing TRKB from dephosphorylating control of PTPσ. Left, In the presence of PNNs, active PTPσ dephosphorylates TRKB and suppresses its signaling. Middle, In the absence of PNNs, PTPσ is inactive and pTRKB is facilitated. Right, Fluoxetine (FLX) disrupts TRKB:PTPσ interaction, promoting TRKB signaling.