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 (PTP, PTPRS), receptor for CSPGs, interacts with TRKB and restricts TRKB phosphorylation. PTP 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 PTP-deficient mice (PTP^+/–). 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 PTP 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 PTP-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 (PTP, PTPRS), a receptor for PNNs, interacts with TRKB and inhibits its phosphorylation, and chondroitinase treatment or deletion of PTP increases TRKB phosphorylation. Antidepressant fluoxetine disrupts the interaction between TRKB and PTP, thereby increasing TRKB phosphorylation. Thus, juvenile-like plasticity induced by both chondroitinase and antidepressant treatment is mediated by TRKB activation in PV⁺ interneurons.

神经周围神经网（PNN）是富含硫酸软骨素蛋白聚糖（CSPG）的细胞外基质结构，可优先包裹含小白蛋白（PV ⁺）的中间神经元。PNNs限制皮层网络的可塑性，但尚不清楚涉及的分子机制。我们发现，由软骨素酶ABC（chABC）介导的PNN去除诱导的成人视皮层眼优势可塑性的重新激活需要PV ^+中神经营养因子受体TRKB的完整信号传导神经元。此外，我们证明chABC可增加TRKB磷酸化（pTRKB），而PNN组件聚集蛋白聚糖可减弱培养物中皮层神经元中脑源性神经营养因子（BDNF）诱导的pTRKB。我们进一步发现蛋白质酪氨酸磷酸酶（PTP，PTPRS），CSPG的受体，与TRKB相互作用并限制TRKB磷酸化。PTP缺失增加TRKB的磷酸化在体外和在体内在雄性和雌性小鼠，和少年等可塑性被保持在成人PTP缺陷小鼠的视觉皮层（PTP ^+/-）。已知抗抑郁药氟西汀可促进TRKB磷酸化并在成人大脑中重新开放关键时期样可塑性，它通过与TRKB跨膜结构域结合而破坏TRKB与PTP之间的相互作用。我们建议chABC和氟西汀在成人视皮层中通过抑制PTP-CSPG复合物对TRKB的去磷酸化来促进PV ⁺神经元中的TRKB信号，从而重新打开关键时期样可塑性。

意义声明可以通过软骨素酶治疗或慢性抗抑郁药治疗破坏神经周神经网（PNN），从而恢复成人视皮质的关键时期样可塑性。我们现在显示，软骨素酶和氟西汀的作用是由神经营养蛋白受体TRKB在含小白蛋白的（PV ⁺）中间神经元中介导的。我们发现，软骨素酶诱导的视觉皮层可塑性取决于PV ^+中的TRKB神经元。蛋白质酪氨酸磷酸酶（PTP，PTPRS）是PNN的受体，与TRKB相互作用并抑制其磷酸化，软骨素酶处理或PTP缺失会增加TRKB磷酸化。抗抑郁药氟西汀会破坏TRKB和PTP之间的相互作用，从而增加TRKB的磷酸化。因此，由软骨素酶和抗抑郁药治疗诱导的少年样可塑性是由PV ^+中神经元中的TRKB激活介导的。