Trapped in the net: restriction of TRKB function by perineuronal nets inhibits plasticity in the central nervous system

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Title: Trapped in the net: restriction of TRKB function by perineuronal nets inhibits plasticity in the central nervous system
Author: Lesnikova, Angelina
Contributor: University of Helsinki, Faculty of Biological and Environmental Sciences
Doctoral Programme in Integrative Life Science
Publisher: Helsingin yliopisto
Date: 2021-11-29
Language: en
Thesis level: Doctoral dissertation (article-based)
Abstract: Induction of neuronal plasticity by drugs and physiological mechanisms has been an important topic in the modern neuroscience investigations due to its potential to restore functions in a wide range of disorders. However, significant progress in this area has been hampered by the lack of knowledge on the precise mechanisms and underlying molecular pathways. Perineuronal nets (PNNs), extracellular matrix structures that are particularly abundant around parvalbumin-containing (PV+) neurons, mature towards the end of the critical period in the brain development and inhibit neuronal plasticity. However, molecular pathways affected by PNN composition are not well known. On the other hand, tropomyosin receptor kinase B (TRKB), receptor for brain-derived neurotrophic factor (BDNF), is a well-recognized facilitator of plastic changes in the central nervous system. Whether these two opposing mechanisms converge on any common molecular pathway has not been identified previously. In the first study, we identified that perineuronal nets inhibit flexibility of neuronal cells and circuits through binding to receptor-like protein tyrosine phosphatase sigma (PTPσ), which subsequently dephosphorylates and inactivates TRKB. Specifically, we found that PNN component aggrecan restricts TRKB phosphorylation, while PNN removal by enzymatic activity of chondroitinase ABC (chABC) increases TRKB phosphorylation in neuronal cultures in vitro. We also found that a well-known ability of chABC to induce ocular dominance plasticity in the adult brain is dependent on TRKB, as mice deficient for TRKB in parvalbumin neurons (PV-TRKB+/-) do not exhibit enhanced plasticity in the visual cortex after chondroitinase treatment. We discovered that genetic knockdown of the PNN receptor PTPσ facilitates TRKB activation in vitro and in vivo, and that adult PTPσ+/- mice have juvenile-like plasticity in the visual cortex. We confirmed that TRKB and PTPσ display interaction in vitro, and identified that interaction occurs in the transmembrane domain. Finally, we found that the interaction between TRKB and PTPσ is diminished by antidepressant fluoxetine in vitro and in vivo. Altogether, our study suggests that chABC and antidepressant treatment induce plasticity through activation of TRKB by relaxing dephosphorylating control of PTPσ over it. In the second study, we focused on studying the molecular and behavioral phenotype of increased tonic plasticity displayed by genetic deficiency of PTPσ. We found that PTPσ+/- mice have increased phosphorylation of PLCγ1 but not Akt or Erk, suggesting that PTPσ specifically modulates PLCγ1 but not the other TRKB downstream signaling pathways. We did not find any changes in the expression levels of PSD-93, PSD-95 or in the number of excitatory synapses in their brain, suggesting that their phenotype cannot be explained by an altered number of synapses. We carried out a battery of behavior tests and discovered that PTPσ+/- mice have improved short-term and deteriorated long-term memory, as evident from their performance in the novel object recognition and fear conditioning tests. Finally, these mice do not exhibit any behavior abnormalities in elevated plus maze, open field, marble burying or forced swim test, suggesting that their behavioral changes are specific for tests requiring cognitive flexibility. We propose the term "hyperplasticity" to describe the PTPσ+/- mouse phenotype. Altogether, the current PhD project investigated the interaction between perineuronal nets, transmembrane phosphatase PTPσ and tyrosine receptor kinase TRKB in mediating plasticity in the brain.Neuronal plasticitet är en förmåga hos hjärnan att anpassa sig till miljöförändringar. Farmakologiska behandlingar som syftar till att öka plasticiteten är ofta fördelaktiga vid flera tillstånd, inklusive depression, hjärnskador, neuroutvecklings- och neurodegenerativa störningar. Men exakta mekanismer som orkestrerar plasticitet i hjärnan är inte helt kända. Det aktuella arbetet har belyst de endogena mekanismerna för plasticitet i den vuxna hjärnan, såväl som på de molekylära vägar genom vilka populära metoder för att framkalla plasticitet fungerar. I synnerhet avslöjade det att perineuronala nät, nätliknande strukturer som omger vissa typer av neuroner i hjärnan, begränsar plasticiteten genom att binda till PTPσ, en receptor som finns på neuroncellmembranen. Vid interaktion med perineuronala nät deaktiverar PTPσ TRKB, en receptor för hjärnhärledd neurotrofisk faktor och en viktig plasticitetspromotor i hjärnan. Vi fann också att möss genetiskt modifierade för att ha minskade nivåer av PTPσ i hjärnan uppvisar en fenotyp av "hyperplasticitet". Specifikt lär de sig bättre än vildtypsmössen, men deras minne är instabilt och de glömmer snabbt vad de har lärt sig. Resultaten av denna studie förbättrar vår förståelse av mekanismerna för plasticitet i hjärnan och kan främja utvecklingen av effektiva, säkra och riktade behandlingar för ett brett spektrum av hjärnsjukdomar.
Subject: neuroscience
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