Assessment of Possible Contributions of Hyaluronan and Proteoglycan Binding Link Protein 4 to Differential Perineuronal Net Formation at the Calyx of Held.

Kojiro Nojima,Tetsuya Hori,Haruko Miyazaki,Lydia Vargova,Toshitaka Oohashi

doi:10.3389/fcell.2021.730550

Kojiro Nojima, Tetsuya Hori + Show 3 more

Open Access

https://doi.org/10.3389/fcell.2021.730550

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Abstract

The calyx of Held is a giant nerve terminal mediating high-frequency excitatory input to principal cells of the medial nucleus of the trapezoid body (MNTB). MNTB principal neurons are enwrapped by densely organized extracellular matrix structures, known as perineuronal nets (PNNs). Emerging evidence indicates the importance of PNNs in synaptic transmission at the calyx of Held. Previously, a unique differential expression of aggrecan and brevican has been reported at this calyceal synapse. However, the role of hyaluronan and proteoglycan binding link proteins (HAPLNs) in PNN formation and synaptic transmission at this synapse remains elusive. This study aimed to assess immunohistochemical evidence for the effect of HAPLN4 on differential PNN formation at the calyx of Held. Genetic deletion of Hapln4 exhibited a clear ectopic shift of brevican localization from the perisynaptic space between the calyx of Held terminals and principal neurons to the neuropil surrounding the whole calyx of Held terminals. In contrast, aggrecan expression showed a consistent localization at the surrounding neuropil, together with HAPLN1 and tenascin-R, in both gene knockout (KO) and wild-type (WT) mice. An in situ proximity ligation assay demonstrated the molecular association of brevican with HAPLN4 in WT and HAPLN1 in gene KO mice. Further elucidation of the roles of HAPLN4 may highlight the developmental and physiological importance of PNN formation in the calyx of Held.

Highlights

Perineuronal nets (PNNs) are pericellular coats of condensed matrix that enwrap the cell bodies and dendrites of certain neurons in the adult central nervous system
We evaluated the effect of the genetic deletion of Hapln4 on the differential formation of PNNs using immunohistochemistry and in situ proximity ligation assay (PLA) in Hapln4-KO mice compared with WT mice
Two distinct PNN-type proteoglycan expressions have been reported in the medial nucleus of the trapezoid body (MNTB) (Blosa et al, 2013), namely, brevican localization at the perisynaptic space between the calyx of Held terminals and principal neurons and aggrecan localization at the surrounding neuropil

Summary

Introduction

Perineuronal nets (PNNs) are pericellular coats of condensed matrix that enwrap the cell bodies and dendrites of certain neurons in the adult central nervous system. PNNs are completed at the end of developmental critical periods for experience-dependent plasticity. They contribute to the stabilization of specific connection patterns, limiting plasticity. HAPLN4 in Perineuronal Net Formation been revealed to have myriad actions in many central nervous system functions, including memory, psychiatric disease, and neurodegeneration (Fawcett et al, 2019; Carulli and Verhaagen, 2021). PNNs primarily consist of hyaluronan, chondroitin sulfate proteoglycans (CSPGs) of the lectican family, tenascin-R, and link proteins as a core extracellular matrix (ECM).

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