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Cited by 53Neuroscience and Neuropharmacology ResearchMemory and Neural MechanismsProteoglycans and glycosaminoglycans research

Perineuronal Nets in the Deep Cerebellar Nuclei Regulate GABAergic Transmission and Delay Eyeblink Conditioning

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Hirono, Moritoshi, Watanabe, Satoshi, Karube, Fuyuki, Fujiyama, Fumino, Kawahara, Shigenori, Nagao, Soichi, Yanagawa, Yuchio, Misonou, Hiroaki·2018·The Journal of Neuroscience
DOI 10.1523/jneurosci.3238-17.2018PMC PMC6596157
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Abstract

Perineuronal nets (PNNs), composed mainly of chondroitin sulfate proteoglycans, are the extracellular matrix that surrounds cell bodies, proximal dendrites, and axon initial segments of adult CNS neurons. PNNs are known to regulate neuronal plasticity, although their physiological roles in cerebellar functions have yet to be elucidated. Here, we investigated the contribution of PNNs to GABAergic transmission from cerebellar Purkinje cells (PCs) to large glutamatergic neurons in the deep cerebellar nuclei (DCN) in male mice by recording IPSCs from cerebellar slices, in which PNNs were depleted with chondroitinase ABC (ChABC). We found that PNN depletion increased the amplitude of evoked IPSCs and enhanced the paired-pulse depression. ChABC treatment also facilitated spontaneous IPSCs and increased the miniature IPSC frequency without changing not only the amplitude but also the density of PC terminals, suggesting that PNN depletion enhances presynaptic GABA release. We also demonstrated that the enhanced GABAergic transmission facilitated rebound firing in large glutamatergic DCN neurons, which is expected to result in the efficient induction of synaptic plasticity at synapses onto DCN neurons. Furthermore, we tested whether PNN depletion affects cerebellar motor learning. Mice having received the enzyme into the interpositus nuclei, which are responsible for delay eyeblink conditioning, exhibited the conditioned response at a significantly higher rate than control mice. Therefore, our results suggest that PNNs of the DCN suppress GABAergic transmission between PCs and large glutamatergic DCN neurons and restrict synaptic plasticity associated with motor learning in the adult cerebellum. SIGNIFICANCE STATEMENT Perineuronal nets (PNNs) are one of the extracellular matrices of adult CNS neurons and implicated in regulating various brain functions. Here we found that enzymatic PNN depletion in the mouse deep cerebellar nuclei (DCN) reduced the paired-pulse ratio of IPSCs and increased the miniature IPSC frequency without changing the amplitude, suggesting that PNN depletion enhances GABA release from the presynaptic Purkinje cell (PC) terminals. Mice having received the enzyme in the interpositus nuclei exhibited a higher conditioned response rate in delay eyeblink conditioning than control mice. These results suggest that PNNs regulate presynaptic functions of PC terminals in the DCN and functional plasticity of synapses on DCN neurons, which influences the flexibility of adult cerebellar functions.

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  • Enhanced learning of eyeblink conditioning is observed after ChABC digestion in the deep cerebellar nucleus, although here it is induced by increased GABAergic transmission.

    “Enhanced learning of eyeblink conditioning is also observed after ChABC digestion in the deep cerebellar nucleus, although here it is induced by increased GABAergic transmission [31, 70].”

    From The extracellular matrix and perineuronal nets in memory (2022) · cites this paper as [70]

    The ‘PNN depletion facilitates delay eyeblink conditioning’ section reports higher conditioned-response rates after ChABC injection into the deep cerebellar nuclei. It also reports enhanced inhibitory transmission, but says the combined results ‘suggest’ a link; the Discussion describes a proposed pathway rather than establishing that increased GABAergic transmission caused the learning improvement. Page numbers are unavailable in our copy. (LLM, conf=0.84)

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  • Injection of ChABC or viral vector-containing ChABC to provide long-term depletion of PNNs increases acquisition of eyeblink conditioning but slightly decreases retention of this response when tested about three weeks later.

    “Injection of ChABC [70] or viral vector-containing ChABC to provide long-term depletion of PNNs increases acquisition of eyeblink conditioning [31] but slightly decreases retention of this response when tested about three weeks later.”

    From The extracellular matrix and perineuronal nets in memory (2022) · cites this paper as [70]

    The ‘PNN depletion facilitates delay eyeblink conditioning’ section reports higher conditioned-response rates after ChABC injection in mice, supporting improved acquisition. The paper describes a single ChABC injection, not a ChABC-containing viral vector, and its follow-up was three days of extinction training rather than a retention test about three weeks later. (LLM, conf=0.90)

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Authors
Hirono, M., Watanabe, S., Karube, F., Fujiyama, F., Kawahara, S., Nagao, S., Yanagawa, Y., & Misonou, H.
Affiliations
  • Doshisha University (JP)
  • National Center of Neurology and Psychiatry (JP)
  • University of Toyama (JP)
  • RIKEN Center for Brain Science (JP)
  • Gunma University (JP)
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2018-06-01
Volume
38
Issue
27
Pages
6130-6144
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.3238-17.2018
PMC
PMC6596157
OpenAlex
W2805202206
Semantic Scholar
36503a7842bf2c33789d0e9949740b1cf0fbe50e
Cited by
53
References
77
Citations by year
2026: 4 · 2025: 8 · 2024: 3 · 2023: 8 · 2022: 8 · 2021: 10 · 2020: 7 · 2019: 4 · 2018: 1
FWCI
2.50
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
Japan Society for the Promotion of Science (26350983, 15H01415, 16H03299, 15K01275, 16K07006, 15H05872, 15K06788, 26290002)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
Keywords
perineuronal nets, deep cerebellar nuclei, GABAergic neurotransmission, Purkinje cells, chondroitinase ABC, chondroitin sulfate proteoglycans, inhibitory postsynaptic currents, paired-pulse depression, miniature IPSCs, presynaptic GABA release, synaptic plasticity, delay eyeblink conditioning, cerebellar motor learning, extracellular matrix, glutamatergic neurons
MeSH terms
Animals, Blinking, Cerebellar Nuclei, Conditioning, Classical, Extracellular Matrix, Learning, Male, Mice, Inbred C57BL, Synaptic Transmission, Neuronal Plasticity, Purkinje Cells, Mice, Inhibitory Postsynaptic Potentials

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