Abstract
Because of their abilities to catalyze generation of toxic free radical species, free concentrations of the redox reactive metals iron and copper are highly regulated. Importantly, desired neurobiological effects of these redox reactive metal cations occur within very narrow ranges of their local concentrations. For example, synaptic release of free copper acts locally to modulate NMDA receptor-mediated neurotransmission. Moreover, within the developing brain, iron is critical to hippocampal maturation and the differentiation of parvalbumin-expressing neurons, whose soma and dendrites are surrounded by perineuronal nets (PNNs). The PNNs are a specialized component of brain extracellular matrix, whose polyanionic character supports the fast-spiking electrophysiological properties of these parvalbumin-expressing GABAergic interneurons. In addition to binding cations and creation of the Donnan equilibrium that support the fast-spiking properties of this subset of interneurons, the complex architecture of PNNs also binds metal cations, which may serve a protective function against oxidative damage, especially of these fast-spiking neurons. Data suggest that pathological disturbance of the population of fast-spiking, parvalbumin-expressing GABAergic inhibitory interneurons occur in at least some clinical presentations, which leads to disruption of the synchronous oscillatory output of assemblies of pyramidal neurons. Increased expression of the GluN2A NMDA receptor subunit on parvalbumin-expressing interneurons is linked to functional maturation of both these neurons and the perineuronal nets that surround them. Disruption of GluN2A expression shows increased susceptibility to oxidative stress, reflected in redox dysregulation and delayed maturation of PNNs. This may be especially relevant to neurodevelopmental disorders, including autism spectrum disorder. Conceivably, binding of metal redox reactive cations by the perineuronal net helps to maintain safe local concentrations, and also serves as a reservoir buffering against second-to-second fluctuations in their concentrations outside of a narrow physiological range.
Highlights
Iron is critical for hippocampal development and the differentiation of parvalbumin-expressing neurons whose soma and dendrites are surrounded by perineuronal nets (PNNs), a specialized elabora2 of 24 tion of the extracellular matrix [2,3,4]
In addition to PNN’s ion sorting, anionic shielding and Donnan equilibrium properties, superoxide dismutase (SOD) binds to glycosaminoglycan side chains (GAGs) side chains on the PNN Chondroitin sulfate proteoglycans (CSPGs) and can serve as an additional barrier of protection against oxidative damage caused by increased concentrations of metal cations in the local microenvironment of actively respiring neurons [4,28,39,40]
Rapid scanning Xray fluorescence spectroscopic imaging (RS-XRF) can simultaneously and non-destructively map and quantify multiple metals in the same section in all chemical forms [37]. This analytic technique is demonstrating pathological changes in metal content and distribution in different neurodegenerative diseases [37]; these studies highlight the presence of iron, copper and zinc dyshomeostasis in these disorders
Summary
The type and distribution of CSPGs within the CNS are not uniform; for example, sulfation of N-acetylgalactosamine in both the C4 and C6 positions, referred to as CS-E, is commonly found in cerebral cortex, whereas in cerebellum, a common sulfation pattern is the C6 position of N-acetylgalactosamine and the C2 position of N-glucuronic acid, referred to as CS-D [14,23,26,27] Based on their physico-chemical properties, the dense polyanionic microenvironment created by the long hyaluronic acid backbone and sulfated GAG side chains of the PNN are thought to maintain the fast-spiking properties of GABAergic inhibitory interneurons expressing parvalbumin (PV), a low-affinity, high-capacity Ca2+ -binding protein, and protect against iron-induced oxidative stress and damage [22,28]. A recent in vitro study examined electrophysiological alterations in the excitatory and inhibitory ratio of hippocampal neurons in a quadruple knockout of PNN components (e.g., tenascin-C, Tenascin-R, neurocan, and brevican), supporting the role of PNNs in synaptogenesis [32]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
