Sugarcoated Perineuronal Nets Regulate “GABAergic” Transmission: Bittersweet Hypothesis in Autism Spectrum Disorder

Burket, Jessica A.; Urbano, Maria R.; Deutsch, Stephen I.

doi:10.1097/wnf.0000000000000209

Cited by 17 publications

(40 citation statements)

References 35 publications

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“…Impaired adult neurogenesis is present in many neuropsychiatric and neurodegenerative disorders (Aimone et al 2014; Besnard and Sahay 2016; Burket et al 2017; Kang et al 2016; Lazarov and Marr 2010), and it has been proposed that improving adult neurogenesis could be therapeutic (Jin et al 2004). α7 nAChR dysfunction has been linked to many of these disorders (Dineley et al 2015).…”

Section: Discussionmentioning

confidence: 99%

The α7 nicotinic acetylcholine receptors regulate hippocampal adult-neurogenesis in a sexually dimorphic fashion

Otto

Yakel

2018

Brain Struct Funct

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Disruption in cholinergic signaling has been linked to many environmental and/or pathological conditions known to modify adult neurogenesis. The α7 nAChRs are in the family of cys-loop receptor channels which have been shown to be neuroprotective in adult neurons and are thought to be critical for survival and integration of immature neurons. However, in developing neurons, poor calcium buffering may cause α7 nAChR activation to be neurotoxic. To investigate whether the α7 nAChR regulates neurogenesis in the hippocampus, we used a combination of mouse genetics and imaging to quantify neural stem cell (NSC) densities located in the dentate gyrus of adult mice. In addition, we considered whether the loss of α7 nAChRs had functional consequences on a spatial discrimination task that is thought to rely on pattern separation mechanisms. We found that the loss of α7 nAChRs resulted in increased neurogenesis in male mice only, while female mice showed increased cell divisions and intermediate progenitors but no change in neurogenesis. Knocking out the α7 nAChR from nestin+ NSCs and their progeny showed signaling in these cells contributes to regulating neurogenesis. In addition, male, but not female, mice lacking α7 nAChRs performed significantly worse in the spatial discrimination task. This task was sexually dimorphic in wild-type mice, but not in the absence of α7 nAChRs. We conclude that α7 nAChRs regulate adult neurogenesis and impact spatial discrimination function in male, but not female mice, via a mechanism involving nestin+ NSCs and their progeny.

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Section: Discussionmentioning

confidence: 99%

The α7 nicotinic acetylcholine receptors regulate hippocampal adult-neurogenesis in a sexually dimorphic fashion

Otto

Yakel

2018

Brain Struct Funct

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“…Importantly, "downstream" consequences of impaired transport functions of these "Ptype ATPases", such as interference with synthesis and secretion of cuproenzymes, could play roles in pathogenic processes within the CNS. Further, data suggesting that synaptic release of copper modulates NMDA receptor-mediated neurotransmission, and perineuronal nets (PNNs), which are polyanionic, lattice-like embellishments of the extracellular matrix (ECM), bind redox-reactive metals, such as copper and iron, arouse additional interest in possible regulatory and pathogenic roles of copper in CNS [12][13][14]. PNNs enwrap subpopulations of fast-spiking, parvalbumin-expressing (FS, PV+) GABAergic inhibitory basket cells and pyramidal cells in the neocortex, which are neural elements implicated in the pathogenesis of several major neuropsychiatric disorders, including ASD and schizophrenia [13][14][15][16][17].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, redox-reactive copper is an essential element required for normal CNS function and implicated in pathogenic mechanisms, including disruption of synaptic transmission. Increasingly, physicochemical studies of perineuronal nets (PNNs) and their isolated structural components inform possible functional roles of PNNs in the CNS, such as maintenance of the fast-spiking properties of a subset of parvalbumin-expressing GABAergic interneurons, and modulation of local temporal fluctuations in the binding of redox-reactive metals and their participation in scavenging of toxic free radical species [12,13,19]. The "Donnan-type distribution" of ions created by the "ionic sorting" property of PNNs surrounding fast-spiking parvalbumin-expressing GABAergic Basket cells contributes to generating high-frequency action potentials by pushing Clinward and pulling K + outward [13,19].…”

Section: Discussionmentioning

confidence: 99%

“…Increasingly, physicochemical studies of perineuronal nets (PNNs) and their isolated structural components inform possible functional roles of PNNs in the CNS, such as maintenance of the fast-spiking properties of a subset of parvalbumin-expressing GABAergic interneurons, and modulation of local temporal fluctuations in the binding of redox-reactive metals and their participation in scavenging of toxic free radical species [12,13,19]. The "Donnan-type distribution" of ions created by the "ionic sorting" property of PNNs surrounding fast-spiking parvalbumin-expressing GABAergic Basket cells contributes to generating high-frequency action potentials by pushing Clinward and pulling K + outward [13,19]. Data suggest that Cu 2+ may protect hyaluronic acid (HA), a major component of the PNN with a long anionic, nonsulfated polysaccharide chain composed of repeating alternating disaccharide units of D-glucuronic acid and N-acetyl-glucosamine, by its ability to displace Fe 2+ bound to HA [12,13].…”

Section: Discussionmentioning

confidence: 99%

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Disrupted copper homeostasis: Pathogenic factor in autism spectrum disorder and side effect of valproic acid

Deutsch

Spiegel

Burket

2021

Personalized Medicine in Psychiatry

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A 23 year old male diagnosed with autism spectrum disorder and treated with valproic acid presented with acute onset of hepatic failure; he died less than two months later. Laboratory studies led to a diagnosis of Wilson Disease. The case raised questions about a possible pathogenic role of disrupted copper homeostasis in ASD, and exacerbation of this disruption as a result of treatment with valproic acid. Screening for abnormalities of copper homeostasis may stimulate strategies for therapeutic targeting of a contributing etiological factor and avoidance of contraindicated medications.

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“…Research on the role of the ECM in age-related neuroplasticity has also produced interesting results. Fox et al have shown that, in animals, the previously lost neuroplasticity in visual cortex areas is recovered after the administration of chondroitinase ABC, which enables interneural communication by degrading ECM [126].…”

Section: Perineuronal Nets - Clinical Aspectsmentioning

confidence: 99%

Perineuronal Nets and Their Role in Synaptic Homeostasis

Bosiacki

Gąssowska-Dobrowolska

Kojder

et al. 2019

IJMS

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Extracellular matrix (ECM) molecules that are released by neurons and glial cells form perineuronal nets (PNNs) and modulate many neuronal and glial functions. PNNs, whose structure is still not known in detail, surround cell bodies and dendrites, which leaves free space for synapses to come into contact. A reduction in the expression of many neuronal ECM components adversely affects processes that are associated with synaptic plasticity, learning, and memory. At the same time, increased ECM activity, e.g., as a result of astrogliosis following brain damage or in neuroinflammation, can also have harmful consequences. The therapeutic use of enzymes to attenuate elevated neuronal ECM expression after injury or in Alzheimer’s disease has proven to be beneficial by promoting axon growth and increasing synaptic plasticity. Yet, severe impairment of ECM function can also lead to neurodegeneration. Thus, it appears that to ensure healthy neuronal function a delicate balance of ECM components must be maintained. In this paper we review the structure of PNNs and their components, such as hyaluronan, proteoglycans, core proteins, chondroitin sulphate proteoglycans, tenascins, and Hapln proteins. We also characterize the role of ECM in the functioning of the blood-brain barrier, neuronal communication, as well as the participation of PNNs in synaptic plasticity and some clinical aspects of perineuronal net impairment. Furthermore, we discuss the participation of PNNs in brain signaling. Understanding the molecular foundations of the ways that PNNs participate in brain signaling and synaptic plasticity, as well as how they change in physiological and pathological conditions, may help in the development of new therapies for many degenerative and inflammatory diseases of the brain.

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Sugarcoated Perineuronal Nets Regulate “GABAergic” Transmission: Bittersweet Hypothesis in Autism Spectrum Disorder

Cited by 17 publications

References 35 publications

The α7 nicotinic acetylcholine receptors regulate hippocampal adult-neurogenesis in a sexually dimorphic fashion

The α7 nicotinic acetylcholine receptors regulate hippocampal adult-neurogenesis in a sexually dimorphic fashion

Disrupted copper homeostasis: Pathogenic factor in autism spectrum disorder and side effect of valproic acid

Perineuronal Nets and Their Role in Synaptic Homeostasis

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