Pharmacological and optical activation of TrkB in Parvalbumin interneurons regulate intrinsic states to orchestrate cortical plasticity

Frederike Winkel; Maria Ryazantseva; Mathias B. Voigt; Giuliano Didio; Antonia Lilja; Maria Llach Pou; Anna Steinzeig; Juliana Harkki; Jonas Englund; Stanislav Khirug; Claudio Rivera; Satu Palva; Tomi Taira; Sari E. Lauri; Juzoh Umemori; Eero Castren

doi:10.1038/s41380-021-01211-0

Pharmacological and optical activation of TrkB in Parvalbumin interneurons regulate intrinsic states to orchestrate cortical plasticity

Frederike Winkel, Maria Ryazantseva, Mathias B. Voigt, Giuliano Didio, Antonia Lilja, Maria Llach Pou, Anna Steinzeig, Juliana Harkki, Jonas Englund, Stanislav Khirug, Claudio Rivera, Satu Palva, Tomi Taira, Sari E. Lauri, Juzoh Umemori^*, Eero Castren

^*Corresponding author for this work

Not published at Aalto University

Research output: Contribution to journal › Article › Scientific › peer-review

Abstract

Elevated states of brain plasticity typical for critical periods of early postnatal life can be reinstated in the adult brain through interventions, such as antidepressant treatment and environmental enrichment, and induced plasticity may be critical for the antidepressant action. Parvalbumin-positive (PV) interneurons regulate the closure of developmental critical periods and can alternate between high and low plasticity states in response to experience in adulthood. We now show that PV plasticity states and cortical networks are regulated through the activation of TrkB neurotrophin receptors. Visual cortical plasticity induced by fluoxetine, a widely prescribed selective serotonin reuptake inhibitor (SSRI) antidepressant, was lost in mice with reduced expression of TrkB in PV interneurons. Conversely, optogenetic gain-of-function studies revealed that activation of an optically activatable TrkB (optoTrkB) specifically in PV interneurons switches adult cortical networks into a state of elevated plasticity within minutes by decreasing the intrinsic excitability of PV interneurons, recapitulating the effects of fluoxetine. TrkB activation shifted cortical networks towards a low PV configuration, promoting oscillatory synchrony, increased excitatory-inhibitory balance, and ocular dominance plasticity. OptoTrkB activation promotes the phosphorylation of Kv3.1 channels and reduces the expression of Kv3.2 mRNA providing a mechanism for the lower excitability. In addition, decreased expression and puncta of Synaptotagmin2 (Syt2), a presynaptic marker of PV interneurons involved in Ca2+-dependent neurotransmitter release, suggests lower inputs onto pyramidal neurons suppressing feed-forward inhibition. Together, the results provide mechanistic insights into how TrkB activation in PV interneurons orchestrates the activity of cortical networks and mediating antidepressant responses in the adult brain.

Original language	English
Pages (from-to)	7247-7256
Number of pages	10
Journal	Molecular Psychiatry
Volume	26
Issue number	12
DOIs	https://doi.org/10.1038/s41380-021-01211-0
Publication status	Published - Dec 2021
MoE publication type	A1 Journal article-refereed

Keywords

PERINEURONAL NETS
CRITICAL-PERIOD
SYNAPTIC-TRANSMISSION
ANTIDEPRESSANT DRUGS
NEURONS
ADULT
EXPRESSION
SUBPOPULATIONS
INHIBITION
FLUOXETINE

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10.1038/s41380-021-01211-0

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Winkel, F., Ryazantseva, M., Voigt, M. B., Didio, G., Lilja, A., Llach Pou, M., Steinzeig, A., Harkki, J., Englund, J., Khirug, S., Rivera, C., Palva, S., Taira, T., Lauri, S. E., Umemori, J., & Castren, E. (2021). Pharmacological and optical activation of TrkB in Parvalbumin interneurons regulate intrinsic states to orchestrate cortical plasticity. Molecular Psychiatry, 26(12), 7247-7256. https://doi.org/10.1038/s41380-021-01211-0

@article{4119a4becba240768a377023ec07157a,

title = "Pharmacological and optical activation of TrkB in Parvalbumin interneurons regulate intrinsic states to orchestrate cortical plasticity",

abstract = "Elevated states of brain plasticity typical for critical periods of early postnatal life can be reinstated in the adult brain through interventions, such as antidepressant treatment and environmental enrichment, and induced plasticity may be critical for the antidepressant action. Parvalbumin-positive (PV) interneurons regulate the closure of developmental critical periods and can alternate between high and low plasticity states in response to experience in adulthood. We now show that PV plasticity states and cortical networks are regulated through the activation of TrkB neurotrophin receptors. Visual cortical plasticity induced by fluoxetine, a widely prescribed selective serotonin reuptake inhibitor (SSRI) antidepressant, was lost in mice with reduced expression of TrkB in PV interneurons. Conversely, optogenetic gain-of-function studies revealed that activation of an optically activatable TrkB (optoTrkB) specifically in PV interneurons switches adult cortical networks into a state of elevated plasticity within minutes by decreasing the intrinsic excitability of PV interneurons, recapitulating the effects of fluoxetine. TrkB activation shifted cortical networks towards a low PV configuration, promoting oscillatory synchrony, increased excitatory-inhibitory balance, and ocular dominance plasticity. OptoTrkB activation promotes the phosphorylation of Kv3.1 channels and reduces the expression of Kv3.2 mRNA providing a mechanism for the lower excitability. In addition, decreased expression and puncta of Synaptotagmin2 (Syt2), a presynaptic marker of PV interneurons involved in Ca2+-dependent neurotransmitter release, suggests lower inputs onto pyramidal neurons suppressing feed-forward inhibition. Together, the results provide mechanistic insights into how TrkB activation in PV interneurons orchestrates the activity of cortical networks and mediating antidepressant responses in the adult brain.",

keywords = "PERINEURONAL NETS, CRITICAL-PERIOD, SYNAPTIC-TRANSMISSION, ANTIDEPRESSANT DRUGS, NEURONS, ADULT, EXPRESSION, SUBPOPULATIONS, INHIBITION, FLUOXETINE",

author = "Frederike Winkel and Maria Ryazantseva and Voigt, {Mathias B.} and Giuliano Didio and Antonia Lilja and {Llach Pou}, Maria and Anna Steinzeig and Juliana Harkki and Jonas Englund and Stanislav Khirug and Claudio Rivera and Satu Palva and Tomi Taira and Lauri, {Sari E.} and Juzoh Umemori and Eero Castren",

year = "2021",

month = dec,

doi = "10.1038/s41380-021-01211-0",

language = "English",

volume = "26",

pages = "7247--7256",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Springer",

number = "12",

}

Winkel, F, Ryazantseva, M, Voigt, MB, Didio, G, Lilja, A, Llach Pou, M, Steinzeig, A, Harkki, J, Englund, J, Khirug, S, Rivera, C, Palva, S, Taira, T, Lauri, SE, Umemori, J & Castren, E 2021, 'Pharmacological and optical activation of TrkB in Parvalbumin interneurons regulate intrinsic states to orchestrate cortical plasticity', Molecular Psychiatry, vol. 26, no. 12, pp. 7247-7256. https://doi.org/10.1038/s41380-021-01211-0

TY - JOUR

T1 - Pharmacological and optical activation of TrkB in Parvalbumin interneurons regulate intrinsic states to orchestrate cortical plasticity

AU - Winkel, Frederike

AU - Ryazantseva, Maria

AU - Voigt, Mathias B.

AU - Didio, Giuliano

AU - Lilja, Antonia

AU - Llach Pou, Maria

AU - Steinzeig, Anna

AU - Harkki, Juliana

AU - Englund, Jonas

AU - Khirug, Stanislav

AU - Rivera, Claudio

AU - Palva, Satu

AU - Taira, Tomi

AU - Lauri, Sari E.

AU - Umemori, Juzoh

AU - Castren, Eero

PY - 2021/12

Y1 - 2021/12

N2 - Elevated states of brain plasticity typical for critical periods of early postnatal life can be reinstated in the adult brain through interventions, such as antidepressant treatment and environmental enrichment, and induced plasticity may be critical for the antidepressant action. Parvalbumin-positive (PV) interneurons regulate the closure of developmental critical periods and can alternate between high and low plasticity states in response to experience in adulthood. We now show that PV plasticity states and cortical networks are regulated through the activation of TrkB neurotrophin receptors. Visual cortical plasticity induced by fluoxetine, a widely prescribed selective serotonin reuptake inhibitor (SSRI) antidepressant, was lost in mice with reduced expression of TrkB in PV interneurons. Conversely, optogenetic gain-of-function studies revealed that activation of an optically activatable TrkB (optoTrkB) specifically in PV interneurons switches adult cortical networks into a state of elevated plasticity within minutes by decreasing the intrinsic excitability of PV interneurons, recapitulating the effects of fluoxetine. TrkB activation shifted cortical networks towards a low PV configuration, promoting oscillatory synchrony, increased excitatory-inhibitory balance, and ocular dominance plasticity. OptoTrkB activation promotes the phosphorylation of Kv3.1 channels and reduces the expression of Kv3.2 mRNA providing a mechanism for the lower excitability. In addition, decreased expression and puncta of Synaptotagmin2 (Syt2), a presynaptic marker of PV interneurons involved in Ca2+-dependent neurotransmitter release, suggests lower inputs onto pyramidal neurons suppressing feed-forward inhibition. Together, the results provide mechanistic insights into how TrkB activation in PV interneurons orchestrates the activity of cortical networks and mediating antidepressant responses in the adult brain.

AB - Elevated states of brain plasticity typical for critical periods of early postnatal life can be reinstated in the adult brain through interventions, such as antidepressant treatment and environmental enrichment, and induced plasticity may be critical for the antidepressant action. Parvalbumin-positive (PV) interneurons regulate the closure of developmental critical periods and can alternate between high and low plasticity states in response to experience in adulthood. We now show that PV plasticity states and cortical networks are regulated through the activation of TrkB neurotrophin receptors. Visual cortical plasticity induced by fluoxetine, a widely prescribed selective serotonin reuptake inhibitor (SSRI) antidepressant, was lost in mice with reduced expression of TrkB in PV interneurons. Conversely, optogenetic gain-of-function studies revealed that activation of an optically activatable TrkB (optoTrkB) specifically in PV interneurons switches adult cortical networks into a state of elevated plasticity within minutes by decreasing the intrinsic excitability of PV interneurons, recapitulating the effects of fluoxetine. TrkB activation shifted cortical networks towards a low PV configuration, promoting oscillatory synchrony, increased excitatory-inhibitory balance, and ocular dominance plasticity. OptoTrkB activation promotes the phosphorylation of Kv3.1 channels and reduces the expression of Kv3.2 mRNA providing a mechanism for the lower excitability. In addition, decreased expression and puncta of Synaptotagmin2 (Syt2), a presynaptic marker of PV interneurons involved in Ca2+-dependent neurotransmitter release, suggests lower inputs onto pyramidal neurons suppressing feed-forward inhibition. Together, the results provide mechanistic insights into how TrkB activation in PV interneurons orchestrates the activity of cortical networks and mediating antidepressant responses in the adult brain.

KW - PERINEURONAL NETS

KW - CRITICAL-PERIOD

KW - SYNAPTIC-TRANSMISSION

KW - ANTIDEPRESSANT DRUGS

KW - NEURONS

KW - ADULT

KW - EXPRESSION

KW - SUBPOPULATIONS

KW - INHIBITION

KW - FLUOXETINE

U2 - 10.1038/s41380-021-01211-0

DO - 10.1038/s41380-021-01211-0

M3 - Article

SN - 1359-4184

VL - 26

SP - 7247

EP - 7256

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 12

ER -

Pharmacological and optical activation of TrkB in Parvalbumin interneurons regulate intrinsic states to orchestrate cortical plasticity

Abstract

Keywords

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