biomolecules Review Perineuronal Nets and Metal Cation Concentrations in the Microenvironments of Fast-Spiking, Parvalbumin-Expressing GABAergic Interneurons: Relevance to Neurodevelopment and Neurodevelopmental Disorders Jessica A. Burket 1, Jason D. Webb 1 and Stephen I. Deutsch 2,* 1 Department of Molecular Biology & Chemistry, Christopher Newport University, Newport News, VA 23606, USA; [email protected] (J.A.B.); [email protected] (J.D.W.) 2 Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, 825 Fairfax Avenue, Suite 710, Norfolk, VA 23507, USA * Correspondence: [email protected]; Tel.: +1-757-446-5888 Abstract: Because of their abilities to catalyze generation of toxic free radical species, free concen- trations 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 criti- cal 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 Citation: Burket, J.A.; Webb, J.D.; component of brain extracellular matrix, whose polyanionic character supports the fast-spiking elec- Deutsch, S.I. Perineuronal Nets and trophysiological properties of these parvalbumin-expressing GABAergic interneurons. In addition Metal Cation Concentrations in the to binding cations and creation of the Donnan equilibrium that support the fast-spiking properties Microenvironments of Fast-Spiking, of this subset of interneurons, the complex architecture of PNNs also binds metal cations, which Parvalbumin-Expressing GABAergic may serve a protective function against oxidative damage, especially of these fast-spiking neurons. Interneurons: Relevance to Neurodevelopment and Data suggest that pathological disturbance of the population of fast-spiking, parvalbumin-expressing Neurodevelopmental Disorders. GABAergic inhibitory interneurons occur in at least some clinical presentations, which leads to Biomolecules 2021, 11, 1235. https:// disruption of the synchronous oscillatory output of assemblies of pyramidal neurons. Increased doi.org/10.3390/biom11081235 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. Academic Editor: Francisco J. Muñoz 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 neurode- Received: 22 July 2021 velopmental disorders, including autism spectrum disorder. Conceivably, binding of metal redox Accepted: 14 August 2021 reactive cations by the perineuronal net helps to maintain safe local concentrations, and also serves Published: 18 August 2021 as a reservoir buffering against second-to-second fluctuations in their concentrations outside of a narrow physiological range. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in Keywords: perineuronal net; iron; copper; fast-spiking; parvalbumin; autism spectrum disorder published maps and institutional affil- iations. 1. Introduction There are many proteins participating in binding, transport, and distribution of the Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. redox reactive metals iron and copper throughout the body and across membranes, includ- This article is an open access article ing across neuronal cell membranes and those of specialized organelles within cells. These distributed under the terms and metal cations are also crucial to the catalytic function of many enzymes and mitochondrial conditions of the Creative Commons respiration. For example, synaptic release of free copper also acts locally to modulate Attribution (CC BY) license (https:// neurotransmission [1]. Within the developing brain, iron is critical for hippocampal de- creativecommons.org/licenses/by/ velopment and the differentiation of parvalbumin-expressing neurons whose soma and 4.0/). dendrites are surrounded by perineuronal nets (PNNs), a specialized elaboration of the Biomolecules 2021, 11, 1235. https://doi.org/10.3390/biom11081235 https://www.mdpi.com/journal/biomolecules Biomolecules 2021, 11, x 2 of 25 modulate neurotransmission [1]. Within the developing brain, iron is critical for hippo- campal development and the differentiation of parvalbumin-expressing neurons whose soma and dendrites are surrounded by perineuronal nets (PNNs), a specialized elabora- Biomolecules 2021, 11, 1235 tion of the extracellular matrix [2–4]. Free concentrations of the redox reactive metals2 of 24 iron and copper are highly regulated because of their abilities to catalyze generation of toxic free radical species. The complex architecture of PNNs bind metal cations, which serves a protectiveextracellular function matrix against [2–4]. Free oxidative concentrations damage, of theespecially redox reactive oxidative metals damage iron and of copper the fast- spikingare highly neurons regulated with their because dense of theirconcentration abilities to of catalyze rapidly generation respiring of mitochondria toxic free radical [5–8]. It species. The complex architecture of PNNs bind metal cations, which serves a protective is conceivable that the binding of these metal redox reactive cations not only contributes function against oxidative damage, especially oxidative damage of the fast-spiking neurons to maintenancewith their dense of their concentration safe local of concentratio rapidly respiringns, but mitochondria also serves [5– as8]. a It reservoir is conceivable that can “buffer”that the against binding second-to-second of these metal redox fluctuations reactive cations in their not concentrations only contributes and to maintenance availability [4]. ofHistofluorescent-staining their safe local concentrations, of PNNs but also with serves specific as a reservoirplant lectins that is can a useful “buffer” morphologic against approachsecond-to-second to identify fluctuations subpopulations in their concentrationsof fast-spiking, and parvalbumi availability [n-expressing4]. (FSPV+) GABAergicHistofluorescent-staining interneurons, as well of PNNsas population with specifics of plantpyramidal lectins isneurons. a useful morphologicWithin the cere- bralapproach cortex and to identifyhippocampus, subpopulations fast-spiking, of fast-spiking, PV-expressing parvalbumin-expressing GABAergic interneurons (FSPV+) are the GABAergicmost populous interneurons, neurons as enwrapped well as populations by PNNs, of pyramidal which is neurons. consistent Within with the an cerebral important cortex and hippocampus, fast-spiking, PV-expressing GABAergic interneurons are the role of the PNN in maintaining and protecting energy-efficient and rapid information most populous neurons enwrapped by PNNs, which is consistent with an important transfer.role of These the PNN interneurons in maintaining regulate and the protecting synchronous energy-efficient oscillatory and output rapid of information assemblies of pyramidaltransfer. output These interneuronsneurons that regulate are computed the synchronous “upward” oscillatory into gamma-band output of assemblies synchrony of 30–80of pyramidalHz [4,9–11]. output Gamma-band neurons that synchrony are computed across “upward” cortical intoareas gamma-band facilitates functional synchrony con- nectivityof 30–80 between Hz [4,9 –them11]. Gamma-band and is necessary synchrony for performance across cortical of areasmany facilitates higher cognitive functional func- tions,connectivity such as working between memory, them and response is necessary sele forction, performance object representation, of many higher attention cognitive and sensorimotorfunctions, suchintegration, as working among memory, other response functions selection, [4,9,10,12–14]. object representation, Disturbance attentionof these fast- spiking,and sensorimotor parvalbumin-expressing integration, among neurons other lead functionss to disruption [4,9,10,12– 14of]. the Disturbance synchronous of these oscilla- fast-spiking, parvalbumin-expressing neurons leads to disruption of the synchronous tory output of assemblies of pyramidal neurons that ultimately impact functional connec- oscillatory output of assemblies of pyramidal neurons that ultimately impact functional tivityconnectivity and higher and cognitive higher cognitive functions functions (Figure (Figure 1). 1). Figure 1. Regulation of synchronous oscillatory activity of pyramidal cell neurons by GABAergic interneurons. Figure 1. Regulation of synchronousThe figure oscillatory depicts activity a fast-spiking of pyramidal parvalbumin-expressing cell neurons by GABAergic GABAergic interneurons. projection onto an assembly of neocortical pyramidal output neurons. The inhibitory input of the GABAer- Biomolecules 2021, 11, 1235 3 of 24 gic projection synchronizes the oscillatory output of the assembled pyramidal neurons, which, in turn, is computed upward into rhythms that may mediate functional connectivity across disparate regions of the cerebral cortex. Conceivably, abnormalities of the handling of redox-reactive metals by the PNNs surrounding the neurons in this circuit would lead to impairment of the