Cited by 124Neuroscience and Neuropharmacology ResearchNeural dynamics and brain functionNeurogenesis and neuroplasticity mechanisms

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Perineuronal Nets Regulate the Inhibitory Perisomatic Input onto Parvalbumin Interneurons and γ Activity in the Prefrontal Cortex

Open access
Carceller, Hector, Guirado, Ramon, Ripolles-Campos, Edna, Teruel-Marti, Vicent, Nacher, Juan·2020·The Journal of Neuroscience

Abstract

Parvalbumin-expressing (PV+) interneurons play a key role in the maturation and synchronization of cortical circuitry and alterations in these inhibitory neurons, especially in the medial prefrontal cortex (mPFC), have been found in different psychiatric disorders. The formation of perineuronal nets (PNNs) around many of these interneurons at the end of the critical periods reduces their plasticity and sets their connectivity. Consequently, the presence of PNNs must have an important impact on the synaptic input and the physiology of PV+ cells. In the present study, we have found that in adult male mice, prefrontocortical PV+ cells surrounded by PNNs show higher density of perisomatic excitatory and inhibitory puncta, longer axonal initial segments (AISs), and higher PV expression when compared with PV+ cells lacking PNNs. In order to better understand the impact of PNNs on the connectivity and physiology of PV+ interneurons in the mPFC, we have digested enzymatically these structures and have found a decrease in the density of inhibitory puncta on their perisomatic region but not on the PV+ perisomatic puncta on pyramidal neurons. Moreover, extracellular recordings show that the digestion of PNNs induces a decrease in γ activity, an oscillation dependent on PV+ cells, in the mPFC of anesthetized mice. Our results suggest that the presence of PNNs enwrapping PV+ cells regulates their inhibitory input and has a potent influence on their activity. These results may be relevant for psychiatric research, given the alterations in PNNs, PV+ interneurons and their physiology described in different mental disorders. SIGNIFICANCE STATEMENT Parvalbumin-expressing (PV+) interneurons are surrounded by specializations of the extracellular matrix, the perineuronal nets (PNNs). PNNs regulate the development and plasticity of PV+ cells and, consequently, their presence must influence their synaptic input and physiology. We have found, in the adult prefrontal cortex (PFC), substantial differences in the structure and connectivity of PV+ interneurons depending on the presence of PNNs. The depletion of PNNs from the PFC has also a potent effect on the connectivity of PV+ cells and on neural oscillations that depend on these cells. These findings are relevant to understand the role of PNNs in the adult brain and in certain psychiatric disorders in which alterations in PNNs and PV+ interneurons have been described.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In adult male mice, medial prefrontal parvalbumin interneurons wrapped by perineuronal nets differ from those without nets in PV expression, perisomatic synaptic input, and axon initial segment length. Enzymatic removal of perineuronal nets reduces inhibitory perisomatic input onto these interneurons and lowers high- and fast-gamma activity in prelimbic cortex.

Key findings

  • PV1 cells with PNNs had higher PV immunofluorescence (p = 0.0310), a positive PV–WFA intensity correlation (r = 0.5585, p < 0.0001), greater densities of VGAT+ (p = 0.046) and VGAT/PV+ (p = 0.008) perisomatic puncta, greater VGLUT1+ puncta (p = 0.031), and longer AISs (p = 0.021) than PV1 cells without PNNs; CB1r+ (p = 0.980), VGLUT2+ (p = 0.887), and VGLUT1/VGAT ratio (p = 0.142) did not differ.
  • ChABC eliminated WFA labeling across the mPFC at 2 and 4 days, with slight recovery by 6 days; analyses were performed 4 days after injection.
  • After ChABC, PV1 cells showed decreased SYN+ (p = 0.008), VGAT+ (p = 0.0162), and VGAT/PV+ (p = 0.0083) perisomatic puncta, increased AIS length (p = 0.026), and a shifted VGLUT1/VGAT ratio (p = 0.0181), while VGLUT1+ puncta (p = 0.7700), PV intensity (p = 0.694), PV+ puncta on pyramidal neurons (p = 0.3023), CamkII intensity (p = 0.7269), and neuropil puncta densities were unchanged.
  • ChABC reduced FosB expression in PV1 and pyramidal cells (both p < 0.0001) and reduced high-gamma (p = 0.003) and fast-gamma (p = 6 × 10⁻⁵) power without changing low-gamma (p = 0.65), theta–gamma modulation index (p = 0.109 high, p = 0.6754 fast), or c-Fos in PV1 (p = 0.1152) and pyramidal cells (p = 0.0812).

Methods

  • Thirty three-month-old male PV-TdT mice were used: 4 for descriptive PNN/PV1 analysis and 26 for ChABC experiments, with 14 for histology and 12 for electrophysiology.
  • Mice received bilateral stereotaxic injections of ChABC or control penicillinase into the mPFC; tissue was analyzed by fluorescence immunohistochemistry, confocal imaging, and quantification of perisomatic puncta, AIS length, PV, FosB, and c-Fos.
  • Under urethane anesthesia, local field potentials were recorded from prelimbic cortex during a tail-pinch protocol; spectral power and theta–gamma modulation index were analyzed.

Limitations

  • The paper does not include a dedicated limitations section.
  • Evident from the text: only male mice were studied, recordings were performed under anesthesia, and the main ChABC analyses used a single 4-day post-injection time point.
  • The authors note that their neuropil findings differ from another study, which they attribute possibly to cortical region, survival time, or presynaptic versus postsynaptic markers analyzed.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1523/jneurosci.0291-20.2020

Cites

42 of 42 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

46 Own result · 14 Own interpretation · 8 Partly supported · 7 No full text of the sources · 4 Supported · 3 Supported so far · 2 Sources not found · 1 Couldn’t confirm · 1 Not checked yet · 1 Own method · accuracy not yet measured

  • Probably not a substantial claim. 24
  • It may state two separate claims as one. 17
  • The quote only partly states this claim. 2
36 of 36
  • The paper relies on this without support.

    The effects of ChABC on PNNs and neuronal connectivity remain unexplored in the medial prefrontal cortex.

    “The effects of ChABC have been extensively studied in sensory systems but remain unexplored in high-order areas such as the medial prefrontal cortex (mPFC), whose dysfunction underlies different psychiatric disorders.”
  • The paper relies on this without support.

    The impact of the presence of PNNs on the AIS of PV1 cells remains to be explored.

    “Nevertheless, this parameter has only been studied on excitatory neurons and the impact of the presence of PNNs on the AIS of PV1 cells still remains to be explored.”
  • The paper relies on this without support.

    ChABC treatment specifically digests PNNs without affecting other extracellular matrix components or cellular processes.

    “After ChABC treatment in the PFC, our results showed a decrease of g oscillations, maintaining the u -g coupling.”
  • The paper relies on this without support.

    The density of perisomatic puncta expressing inhibitory markers reflects the strength or number of functional inhibitory synapses onto PV1 cells.

    “Our results show a positive correlation of PV expression and the density of perisomatic inhibitory puncta onto PV1 cells.”
  • The paper relies on this without support.

    PV fluorescence intensity is a valid measure of PV expression level in PV1 cells.

    “We also describe a positive correlation between PNNs and PV expression”
  • The paper relies on this without support.

    WFA labeling specifically identifies PNNs.

    “representative immunostaining of the expression of PV and WFA in PrL”
6 of 6

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Metadata

Authors
Carceller, H., Guirado, R., Ripolles-Campos, E., Teruel-Marti, V., & Nacher, J.
Venue
The Journal of Neuroscience
Published
2020-05-26
Volume
40
Issue
26
Pages
5008-5018
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
OpenAlex
W3031913802
Cited by
112
References
42
Citations by year
2026: 22 · 2025: 18 · 2024: 18 · 2023: 17 · 2022: 18 · 2021: 19
FWCI
6.18
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Repository of Digital Objects for Teaching Research and Culture (University of Valencia) (submittedVersion)
Funders
  • Ministerio de Ciencia, Innovación y Universidades (BFU2016-77691-C2, RTI2018‐098269‐B‐I00, IJCI-2016-27758, FPU15, RTI2018, SAF2015-68436-R)
  • Ministerio de Economía y Competitividad (SAF2015-68436-R, C2-2-P)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
perineuronal nets, parvalbumin interneurons, medial prefrontal cortex, perisomatic inhibition, gamma oscillations, axon initial segment, extracellular matrix, interneuron connectivity, mental illness, cortical circuits, adult brain plasticity, critical period, pyramidal neurons, extracellular recording, mice
MeSH terms
Animals, Extracellular Matrix, Interneurons, Male, Mice, Inbred C57BL, Neuronal Plasticity, Parvalbumins, Prefrontal Cortex, Mice, Gamma Rhythm

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