Attenuation of the extracellular matrix increases the number of synapses but suppresses synaptic plasticity through upregulation of SK channels
Graphical abstract
Introduction
The components of the extracellular matrix (ECM) form a molecular meshwork in the extracellular space of the brain. The major components of the ECM are hyaluronic acid, chondroitin sulfate proteoglycans (CSPGs), link proteins such as hyaluronan, and proteoglycan link protein 1 (HAPLN1/CRTL1), and glycoproteins such as tenascinR, which cross-link CSPGs and stabilize ECM structure [1]. The ubiquitous localization of ECM allows it to broadly affect neuronal function, both through mechanical and electrical regulation of diffusion in the extracellular space, as well as by interacting with several transmembrane receptors and channels [2].
During prenatal and early postnatal brain development, the ECM provides either adhesive or repellent cues that control cell migration and navigation of growing axons. These processes involve signaling through a diverse group of transmembrane receptors, such as integrins [3], ApoER2, VLDL, EphB [4,5], and RPTPσ [6,7]. In the mature brain, a number of ECM molecules and ECM receptors trigger various biochemical cascades that regulate neuronal function [8]. Attenuation of the ECM in the adult brain can potentially restore the brain to an immature state and promote (re-)wiring [9]. Hence, manipulation of the ECM has been suggested as a way to stimulate brain repair after injury and boost brain plasticity [10,11]. Nevertheless, the role of ECM in synaptic plasticity remains controversial [12,13]. Initial studies suggested that acute enzymatic digestion of CSPGs with chondroitinase ABC (ChABC) impaired both long-term potentiation (LTP) and depression (LTD) in the CA1 region of the hippocampus [14]. Similarly, LTP in hippocampal CA1 neurons was reduced by a deficiency in the ECM components brevican, or tenascin-R reduced [[14], [15], [16], [17]], as well as after acute enzymatic digestion of hyaluronic acid with hyaluronidase [18]. Moreover, intra-hippocampal injection of hyaluronidase impaired contextual fear conditioning [18]. These studies demonstrate that ECM attenuation may disrupt synaptic plasticity and some forms of learning and memory. On the other hand, mice deficient in CSPG phosphacan/RPTPbeta exhibit increased LTP [19]. HAPLN1 knockout mice retain high juvenile-type levels of ocular dominance plasticity in adulthood [20] and exhibit enhanced long-term object recognition memory and LTD in the perirhinal cortex [21]. Similarly, recognition memory is enhanced following ChABC injection [21]. These findings suggest that genetic or enzymatic attenuation of the ECM may promote some forms of synaptic plasticity and learning.
Here, we resolve this controversy by showing that ECM attenuation with ChABC increases the number of ‘plastic’ glutamatergic synapses onto CA1 pyramidal neurons while at the same time reducing neuronal excitability through the upregulation of small conductance Ca2+-activated K+ (SK) channels that suppress LTP.
Section snippets
ECM attenuation increases the number of glutamatergic synapses onto CA1 pyramidal neurons
Hippocampal slices from two mice (two slices per mouse) were treated with either ChABC or a sham solution and were used for serial section electron microscopy. Dendritic spines and axonal boutons were visually identified, manually segmented, and reconstructed in three-dimensions (3D, Fig. 1a,b). To avoid selection bias, the number of spines and boutons was calculated in five randomly selected block series of each reconstruction (Fig. 1c,d; Fig. S1). The spines were divided into two groups:
Discussion
The ECM holds neighboring cells together and stabilizes synapses [34,35]. However, the ECM also shields the cell surface, making it more difficult for new synapses to form [9,36]. The effect of ECM removal on dendritic spines has been previously shown in neuronal culture and organotypic slices, where it increases spine motility, spine extension, and network rewiring [9]. In physiological conditions, ECM is cleaved and remodeled by matrix metalloproteinases (MMPs) [37,38]. MMP-9 has been shown
Animals
All experiments were performed in 4- to 6-week-old C57BL/6 J male mice. Animal procedures were conducted in accordance with regulations and ethical animal research standards defined by the ethical committee of the Lobachevsky State University of Nizhny Novgorod.
Hippocampal slice preparation
Animals were killed by cervical dislocation and then decapitated. The brains were exposed and chilled with ice-cold solution containing (in mM) 87 NaCl, 2.5 KCl, 7 MgCl2, 1.25 NaH2PO4, 26.2 NaHCO3, 0.5 CaCl2, 25 D-glucose, and 50
Data availability
All data needed to evaluate the conclusions in the article are present in the article and/or supplementary materials. Additional data related to this article may be requested from the authors.
CRediT authorship contribution statement
Yulia Dembitskaya: Conceptualization, Methodology, Formal analysis, Investigation, Writing - original draft. Nikolay Gavrilov: Formal analysis. Igor Kraev: Formal analysis, Writing - original draft. Maxim Doronin: Investigation, Formal analysis. Yong Tang: Funding acquisition, Writing - review & editing. Li Li: Writing - review & editing. Alexey Semyanov: Conceptualization, Methodology, Formal analysis, Writing - original draft, Supervision, Funding acquisition.
Declaration of Competing Interest
The authors declare no conflict of interest
Acknowledgments
The authors are grateful to Prof. Alexander Dityatev for the discussion of preliminary results, Dr Inseon Song for help with electrophysiology experiments and Ms Inna Golyagina for help with the analysis of electron microscopy images. AS and YT are supported by RFBR grant 21-54-53018 for the NSFC-BFBR project.
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