Chondroitin sulfate, a major component of the perineuronal net, elicits inward currents, cell depolarization, and calcium transients by acting on AMPA and kainate receptors of hippocampal neurons

Abstract

Chondroitin sulfate (CS) proteoglycans (CSPGs) are the most abundant PGs of the brain extracellular matrix (ECM). Free CS could be released during ECM degradation and exert physiological functions; thus, we aimed to investigate the effects of CS on voltage-and current-clamped rat embryo hippocampal neurons in primary cultures. We found that CS elicited a whole-cell Na + -dependent inward current (I CS ) that produced drastic cell depolarization, and a cytosolic calcium transient ([Ca 2+ ] c ). Those effects were similar to those elicited by a-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and kainate, were completely blocked by NBQX and CNQX, were partially blocked by GYKI, and were unaffected by MK801 and D-APV. Furthermore, I CS and AMPA currents were similarly potentiated by cyclothiazide, a positive allosteric modulator of AMPA receptors. Because CSPGs have been attributed Ca 2+ -dependent roles, such as neural network development, axon pathfinding, plasticity and regeneration after CNS injury, CS action after ECM degradation could be contributing to the mediation of these effects through its interaction with AMPA and kainate receptors.

Loss of Chondroitin Sulfate Modification Causes Inflammation and Neurodegeneration in skt Mice

“…Within the brain, CSPGs are the most abundant part of the ECM and different types of CSPGs are localized to intercellular spaces between neurons and glia (Dityatev et al 2007;Bonneh-Barkay and Wiley 2009;Maroto et al 2013). Additionally, perineuronal nets (PNNs) are CSPG-rich ECM lattice-like structures that envelop subpopulations of neurons in certain brain regions including the hippocampus (Celio and Blümcke 1994;Deepa et al 2006;Maroto et al 2013) and play key roles in neural development, synaptogenesis, neuroprotection, and synaptic plasticity. The degeneration we observed in the Chsy1 skt hippocampus indicates that modification of proteins by CHSY1 is important for maintaining neuronal health in the brain, and lack of those CS modifications can lead to neurodegeneration.…”

Semaphorin 3A Binds to the Perineuronal Nets via Chondroitin Sulfate Type E Motifs in Rodent Brains

“…However, it is unlikely that all the effects of PNNs are mediated through this mechanism. Recent reports have implicated the role of PNNs in the modulation of synapses through AMPA receptor mobility, which is unlikely to involve Sema3A (56,57). Moreover, several CSPG receptors, such as protein-tyrosine phosphatase-, contactin, and Nogo receptor 3, are also widely expressed in the CNS (51)(52)(53)(54).…”

Degradation of extracellular chondroitin sulfate delays recovery of network activity after perturbation

“…Although it is unclear how CSPGs mediate their effects on neuronal excitability, there are three categories of evidence for potential mechanisms in other systems: cation buffering (Hrabětová et al 2009;Vigetti et al 2008), interaction with cell-surface receptors or channels (Maroto et al 2013;Snow et al 1994), and binding of growth factors for later presentation to cellular receptors (Deepa et al 2002(Deepa et al , 2004Kantor et al 2004). The lack of a clear change in the ongoing pyloric rhythm in the intact STNS after chABC treatment suggests that ion buffering is an unlikely mechanism in our system.…”

“…CSPGs are produced locally by neurons and glia (Giamanco and Matthews 2012), with dependence on cellular activity patterns (Lander et al 1997) via Ca 2ϩ influx (Dityatev et al 2007). Structural differences within the CSPG family are cell type specific (Lander et al 1997) and result in diverse functional roles, such as alternately preventing or encouraging neuronal structural plasticity and pathfinding (Balmer et al 2009;Fongmoon et al 2007;Gogolla et al 2009;Kwok et al 2012;Snow et al 1994), binding and presentation of growth factors (Galtrey and Fawcett 2007), and modulation of ion channel properties (Dityatev et al 2007;Maroto et al 2013;Snow et al 1994;Vargas and De-Miguel 2009;Vigetti et al 2008). The type specificity, activity dependence, and diverse functional roles of CSPGs together suggest a way by which changes in activity output can feed back onto regulatory mechanisms-the hallmark of a homeostatic process.…”