Prerpints.org logo
Preprint
Review

Functional Myelin in Cognition and Neurodevelopmental Disorders

Altmetrics

Downloads

249

Views

115

Comments

0

A peer-reviewed article of this preprint also exists.

Submitted:

04 December 2023

Posted:

06 December 2023

Read the latest preprint version here

Alerts
Abstract
In vertebrates, oligodendrocytes (OLs) are glial cells of the central nervous system (CNS) responsible for the formation of the myelin sheath that surrounds the axons of neurons. The myelin sheath plays a crucial role in the transmission of neuronal information by promoting the rapid saltatory conduction of action potentials and providing neurons with structural and metabolic support. Saltatory conduction, first described in the peripheral nervous system (PNS), is now generally recognized as a universal evolutionary innovation to respond quickly to the environment: myelin helps us think and act fast. However, the function of myelin in the CNS, particularly in the brain, is not necessarily to act quickly, but rather to act correctly. In this respect, myelin should primarily play a role in synchronizing the different neuronal networks, a synchrony that occurs in the form of oscillations (or rhythms) relevant for specific information processing. Interestingly, myelin has been directly involved in different types of cognitive processes relying on brain oscillations, and myelin plasticity is currently considered to be part of the fundamental mechanisms for memory formation and maintenance. However, despite ample evidence showing the involvement of myelin in cognition and neurodevelopmental disorders characterized by cognitive impairments, the link between myelin, brain oscillations, cognition and disease is not yet fully understood. In this review, we aim to highlight what is known and what remains to be explored to understand the role of myelin in high order brain processes.
Keywords: 
Subject: Biology and Life Sciences  -   Neuroscience and Neurology

Introduction

In the central nervous system (CNS), oligodendrocytes (OLs) are responsible for the production and maintenance of the myelin sheath. OLs originate from oligodendrocyte precursor cells (OPCs), which arise in the embryonic (ventral OPCs) and postnatal (dorsal OPCs) mouse telencephalon in distinct successive waves [1,2]. OPCs also persist as a major pool of progenitors in the adult brain long after oligodendrogenesis, and promote remyelination when necessary [3,4,5,6,7,8,9]. However, they should not be constrained to their OL progenitor function as they are arising as circuit regulators in the parenchyma with functions ranging from neuronal migration to glial scar formation [10] extensively reviews these functions). Along the same line, an extensive body of evidence links OLs to a variety of roles such as energy metabolism, neuroprotection, axonal maintenance and information processing [11,12,13,14]. These roles of OLs have often been highlighted by studying myelin.
The myelin sheath is a highly specialized multilamellar membrane that wraps axons. Central myelin is structured by an ensemble of compact interconnected lamellae of membrane that contact the axon through terminal loops forming the axo-glial paranodal junction directly followed by the juxtaparanode located beneath the compacted myelin of the internode [15,16]. What we usually refer to as the myelin sheath is the single entity formed by the paranodes, juxtaparanodes and the internode. Adjacent myelin sheaths are separated by nodes of Ranvier (NORs) [17], unmyelinated regions where the nerve fiber is laid bare and frequently contacted by other glial cells including astrocytes [18,19], OPCs [20] and microglia [21,22]. Myelin’s high compartmentalization allows a distinctive sheath-axon interaction that serves various functional ends such as the distribution of glial metabolites [16,23]. In intimate relationship with the unmyelinated segments or NORs, the myelin sheath enables action potential regeneration and propagation along fibers of varying lengths, resulting in saltatory conduction, an energy-, space- and time-saving phenomenon.
The function of myelin can be approached at two different levels: at the local level, which consists of isolating axons, supporting them and ensuring bidirectional axo-glial communication, and at the global level, which orchestrates the interconnection of neuronal assemblies and, at a higher level, the functional brain hubs for complex information processing. In this review, we will first introduce some general concepts about the role of myelin in action potential conduction and axonal metabolism. Next, we will discuss the implications of myelin in prefrontal cortex function and cognition, and assess whether myelination might modulate neuronal network activity and cortical oscillations during the execution of cognitive processes. Finally, we will address the relevance of myelin defects in neurodevelopmental disorders associated with cognitive deficiencies.

Generalities on myelin in conduction and metabolic coupling

Saltatory conduction has long been held as the main phenomenon resulting from myelin sheath wrapping around electrically active axons [24,25]. In electrophysiological terms, myelin works such wonders by decreasing the capacitance of the axolemma while increasing resistance to ion flow. This achieves two important features: (1) conduction speed of action potentials is increased while (2) their electrical properties are maintained throughout the traveled distance. Beyond physical insulation of the axon, the segregation of crucial proteins by the various segments of the sheath directly impacts conduction. Voltage-gated sodium channels (NaV channels) are exclusively stabilized at the NORs by the paranodal axo-glial junction [26,27]. In this small, well-defined region of the axon, an increase in membrane potential up to the threshold potential induces NaV channels opening, generating the strong depolarization (or rising phase) characteristic of the action potential. These channels are then rapidly inactivated allowing potassium channels to repolarize the axon. Different voltage-gated K+ channels (KV3 and Kv7 channels) as well as mechano- and thermo-sensitive K+ channels, two-pore-domain potassium K2P channels, actively drive repolarization (or falling phase) at the nodes [28,29,30], wherein Kv1 channels located in the juxtaparanode contribute to the refractory period enabling high frequency firing [31,32]. Directly underneath the sheath, OL expression of inwardly rectifying K+ channels (Kir channels) allows K+ buffering which probably help establish axolemma resting potential and excitability, especially in white matter tracts where astrocytes have limited access to axons [33]. Furthermore, it has recently been shown that a type of conduction termed “sub-myelin conduction”, i.e. potential beneath the myelin sheath through the periaxonal and paranodal spaces, is primordial to the spatiotemporal profile of action potential saltation [34], further supporting the notion of an electrophysiological coupling between the axon and its myelin sheaths.
As well as promoting fast conduction, myelin sheaths have emerged as a central component of axon metabolism [14]. Axonal access to energy-rich extracellular metabolites is limited by myelin insulation, so it is the myelin itself that has to supply the energy. Reminiscent of the astrocytic “lactate shuttle”, OLs transport lactate, a product of aerobic glycolysis, into the axon via a pair of specialized monocarboxylate transporters (glial MCT1 and axonal MCT2) allowing a myelin-axon metabolic crosstalk that is relevant both in health and disease [14,35,36]. This axo-glial coupling is highly plastic and follows axon energy needs through the retroactive action of axons on their myelin sheath. Notably, myelin sense axon signals such as glutamate which, by activating NMDA receptors enriched in OL processes, enables these glial cells to tune their energy production to neuronal activation [37,38]. Beyond energy provision, myelinating cells participate to other forms of axo-glial communication that have an impact on metabolism. The activity-dependent release of the neurotransmitter glutamate triggers the secretion by OLs of exosomes carrying a specific protein and RNA cargo that are then internalized by neurons, improving viability and maintaining axonal integrity [39]. Moreover, exosomes released by OLs contribute to antioxidant protection of neurons by secreting ferritin heavy chain (FTH1), a strong iron chelator protein, into the adjacent extracellular space, preventing ferroptosis [40]. Although the functional and metabolic coupling between myelin sheaths and axons is important for the dynamics of myelin-axon interactions, its significance goes far beyond local crosstalk, as it determines the action potential waveform and affects neuronal coding and activity in a network, ultimately influencing information processing in the brain. Over the last decade, myelin has emerged as an important component of plasticity, memory and learning, moving away from its primary function associated with the transmission and velocity of action potentials.

Myelination heterogeneity in the cortex

The cortex contains a patchwork of differentially myelinated axons belonging to both excitatory and inhibitory neurons. Presence and extent of myelination relies on axon diameter, as OLs tend to extensively myelinate larger axons [41,42] although complex patterns of myelination are also present in sub-diameter threshold axons hinting at other factors driving myelination heterogeneity. OL intrinsic properties [43], neuronal activity [44], as well as neuronal localization and type, all constitute major players in the myelination patterns of the CNS. Amongst these factors, the last of the aforementioned has sparked great interest in understanding myelin properties of local GABAergic interneurons and long projection neurons and their functional repercussions. High throughput electron microscopy which individually traces pyramidal cell proximal axons in the mouse somatosensory cortex uncovered a myelin gradient, with deep layer (V/VI) pyramidal cells displaying a higher myelin coverage compared to superficial layer (II/III) pyramidal neurons. Furthermore, superficial layer pyramidal cells display a distinct longitudinal myelin pattern with myelin sheaths being separated by long unmyelinated gaps (much longer than NORs) (Figure 1A, right; [45]). Local GABAergic fast-spiking, parvalbumin-expressing interneurons (PV interneurons) are also highly myelinated and contribute to a large proportion of gray matter myelin content [46,47,48]. PV interneuron myelin topography is dictated by axonal diameter and interbranch distances in both human and rodent neocortex [49]. However, this myelination is limited to the proximal part of the axon (<3%), so that most of the axon is free of myelin [47], suggesting the existence of other subtle interactions between OLs and specific axonal regions (Figure 1A, right). This myelination serves various purposes during cortical network activity as it is required to sustain high frequency firing and feedforward inhibition, both of which are cardinal to somatosensory processing [50]. Moreover, a flawed myelination of interneurons early in development impairs their autaptic self-inhibitory transmission and results in long-lasting functional defects [51]. Another compelling function of PV interneuron myelin sheaths is the clustering of mitochondria and thus the fine tuning of metabolic requirements during axonal activation [52]. Although white matter myelin has been extensively studied both in health and disease, we should exert caution when extending such findings to gray matter myelination which is protracted, sparse and, as shown above, have topographical and functional complexities not found in white matter tracts [53].

Myelin in cognitive processing

Myelination in the CNS happens in a specific spatial and temporal order in both humans and rodents, and remains plastic and adaptive throughout life [54]. Myelin maturation in the brain progresses in a protracted fashion, from caudal to rostral, so that the prefrontal cortex (PFC) in both humans and rodents is still undergoing myelination well into early adulthood [55,56,57,58,59,60]. It is tempting thus to parallel this “late” maturation of the PFC in terms of myelination with the establishment of higher cognitive functions such as self-identity, sociability and decision making. In fact, correlation between white matter changes and cognitive function over the course of human life establish a link between myelin plasticity and cognitive development. Maturation of fronto-parietal and fronto-striatal white matter pathways correlates with protracted development of cognitive processes during adolescence and early adulthood [61]. Moreover, longitudinal brain imaging studies have shown that white matter volume –reflecting the myelin content and axonal caliber [62]– have a linear volume increase throughout childhood and adolescence [63]. As reported by fractional anisotropy in diffusion tensor MRI, an increase of myelin thickness in frontal white matter positively correlates with increased working memory scope in children [64]. In mice, sociability are related to myelination of the medial PFC (mPFC) as shown by the deleterious effect of social isolation immediately after weaning on both adult mPFC function and myelination [65]. Myelination is therefore a long-lasting process that represents a perfect “substrate” for the maturation and adaptability of cognitive processes. However, although myelination and cognitive development correlate, the underlying mechanisms that link these two processes are not yet fully understood. Among possible mechanism, early neuron-OL interactions may play a decisive role in both developmental myelination and neuronal maturation. In the developing neocortex, OPCs receive transient synaptic inputs from GABAergic interneurons, mainly PV interneurons, that disappear in juvenile mice [66,67]. The genetic inactivation of these neuro-glial synapses at an early stage of postnatal development does not have a major impact on OPC proliferation and differentiation, but leads to significant defects in interneuron myelination and in the maturation of cortical inhibitory circuits, affecting sensory discrimination [48,50]. Furthermore, early GABAB receptor-mediated signaling on OPCs induces the apoptosis of interneuron via the cytokine TWEAK pathway, resulting in the proper PV interneuron density and myelination in the adult [68]. The specific ablation of these receptors in OPCs are associated to an excitation-inhibition imbalance in the mPFC and severe social behavior defects [68]. These studies highlight an important role of early interneuron-OPC communication and interneuron myelination in the establishment of cortical inhibitory circuits and cognitive function (Figure 1A).
Myelin remodeling has taken the spotlight as one of the main drivers of plasticity (both neuronal and behavioral) in the last decade. Myelin establishment during critical periods of early postnatal life is indeed important but not immutable, as OLs drive different myelination patterns in response to neuronal activity and experience throughout the individual’s life [44,69,70,71,72,73,74]. During development, exposure to an early stress caused by maternal separation induces a premature differentiation of OLs in the mPFC along with emotional and object recognition impairments in the adult that can be rescued by the chemogenetic activation of mPFC neurons during the two first weeks of life [75]. Futhermore, the hypomyelination phenotype induced by social isolation in juvenile animals can be reversed in the adult by re-socialization with socially housed mice, but not socially isolated mice [65,76]. Interestingly, prolonged social isolation in the adult specifically induces a decrease in myelin thickness and nuclear heterochromatin in mPFC together with a social defeat, while social re-integration for four weeks resulted in a recovery of myelin transcripts and social interaction behavior [77]. Recent data on other behavioural tasks involving cognition also reveal that myelin is plastic and necessary for a proper behavioral perfomance. For example, spatial memory consolidation during a Morris water maze, resulting from a complex dialogue between PFC areas, such as the anterior cingulate cortex (ACC), and the hippocampus is altered when de novo myelination is prevented in the adult [78]. Along the same line, fear learning and a working memory task (radial arm maze) increase OPC proliferation and myelination, in the mPFC and ACC, respectively [79,80], while the inhibition of myelin formation impairs fear memory recall [80]. In these cognitive processes, reciprocal interactions between myelin and neuronal activity probably comes into play. Myelin plasticity could lead to potentiation or depression of conduction velocity along the axon, which could give rise to differential spike timings that are essential for neuronal network activity [50,72,73]. Myelination also affects synaptic transmission and the excitation-inhibition balance [50,81,82], thus having a potential impact on cortical oscillations and cognition (Figure 1; see next section). It should be noted, however, that some of these interactions may involve subtle mechanisms that go beyond a simple increase or decrease in the amount of myelin, as they may primarily produce a marked change in the length of NORs. Such a change has been observed following a repetitive transcranial magnetic stimulation or the execution of 8-arm radial arm maze task [83]. It should also be considered that it is difficult to disentangle the molecular and cellular pathways as well as the exact role of each player of the myelination process (OPC, OL or myelin) in the observed cognitive processing performance and that further investigation is needed.

Brain oscillations, myelin and cognition

The cerebral cortex is characterized by a sustained activity reflected by the existence of rhythms or oscillations that can be divided into different frequency bands from 0.05Hz to 500Hz [84]. Each band is associated with different neuronal elements, such as membrane properties, population activity or inhibitory state, and its power and frequency can be differently modulated by cognitive processes. Slow oscillations between 0.05Hz to 30Hz result from the coordinated activity of widely distributed neuronal ensembles, as in the case of theta-frequency synchrony (4-12 Hz) between the hippocampus and the mPFC during a spatial working memory task [85]. By contrast, high-frequency oscillations (30-500Hz) involve a small tissue volume and fewer neurons, and are considered a local phenomenon (Figure 1B, left). This is particularly true for gamma oscillations (30-90Hz), which constitute one of the key elements of information coding in the brain and are modulated by cognitive mechanisms such as attention, working memory, cognitive flexibility and social cognition (Figure 1B and C; [86]). Oscillations in the gamma band arises from the fast synchronization of excitatory neuron spiking activity that results from an effective and rapid inhibition, mainly provided by PV interneurons [84,86]. The control of the activity of a population of excitatory neurons by PV interneurons acts like a pacemaker, timing the network for a simultaneous discharge (peak of the cycle) followed by a subsequent silent period (trough of the cycle) [84]. Curiously, gamma rhythm has the same frequency range in several species regardless of the brain size. Furthermore, low- and high-frequency rhythms can be produced at the same time and interact with each other. One of the most widely studied rhythm interactions is the phase-amplitude coupling (PAC), in which the phase of the cycle is modulated by the slow oscillation and the power by the high-frequency oscillation, as first described for theta and gamma rhythms [87]. For example, an increase of theta-gamma PAC power in the mPFC was associated with a better performance in working memory [88].
As mentioned before, myelin plasticity, as another form of activity-dependent plasticity, is relevant not only to nervous system development but also to complex information processing tasks. By its capacity to speed up action potentials and mediate proper spike-timing, it has been widely assumed that myelin influences the synchronization of neuronal ensembles in the brain (Figure 1B, right). On a broader scale, myelin architecture in humans correlates strongly with functional connectivity mediated by neuronal oscillations in the beta and low-gamma bands, reinforcing the idea of a close relationship between myelination and specific functional networks [89]. However, despite emerging evidence for the role of myelin in cognitive processes involving coupling and synchrony, few studies have attempted to disentangle its impact on the generation and maintenance of brain oscillations [90]. Mathematical modeling and simulations have addressed this question and proposed that myelin facilitates the synchronization of axon spikes coming from a distant population of neurons whose activity is correlated [91]. The model predicts that myelin plasticity in response to local action potentials of myelinated axons adjusts the spike temporal dispersion that occurs across these individual axons, thereby optimizing the precision of axonal discharges and promoting synchrony. Although this work supports a role for myelin in the generation of cortical oscillations, the mechanism linking myelination and neuronal synchronization is probably more complex. Indeed, it has been shown that OL-dependent metabolic deficits, independently of myelin content, also alter the temporal precision of neuronal spikes in the auditory system in vivo [12]. Moreover, the heterogeneity of myelination patterns, which is patchy in pyramidal cells [45] and restricted to the proximal part of the axon in PV cells of the cortex (Figure 1A, right; [47]), probably has an impact on axonal conduction and needs to be taken into account. In another experimental study using a cuprizone-induced demyelination mouse model, Dubey et al., assessed the role of myelin in the generation of oscillations in the primary somatosensory cortex [82]. They observed that demyelination selectively amplifies theta power during periods of quiet wakefulness (but not active states) and proposed that this effect was caused, at least in part, by a decrease in the excitability of PV interneurons and fast inhibitory transmission. Furthermore, in vivo optogenetic stimulation of PV interneurons at a low gamma frequency of 30 Hz allows to maintain an oscillatory activity at this frequency in controls, but not following demyelination. By simultaneously recording the ACC region and the hippocampus immediately after contextual fear conditioning, Steadman et al. show that the coupling between spindle oscillations in the prefrontal cortex and sharp wave ripple oscillations in the hippocampus was increased in controls but unchanged in mice with a disrupted oligodendrogenesis [78]. These results indicate that the production of new OLs is required for learning-induced increases in coordinated hippocampal-cortical activity. However, this effect is probably not due to myelin deficiencies since it occurs just after training.
Despite sparse studies on the role of myelin in the synchronization of neuronal networks and brain rhythms, how myelin influences different brain oscillations during behavior, especially during cognitive processes, is largely underexplored. Local in vivo electrophysiological recordings in behaving mice with genetically determined or induced alterations in myelination would be necessary to unravel how myelin is involved in behaviorally modulated cortical rhythms. The detection and quantification of brain oscillations is an advanced field of neuroscience that allows multiple brain areas to be recorded simultaneously, in some cases using more than thousand electrodes, while the animal performs a cognitive task. This type of study represents a major challenge and a future line of research in the field of myelin.

Myelin in neurodevelopmental diseases (ndds)

As an early onset phenomenon with a protracted evolution throughout life, myelin has emerged as a potential key player in NDDs, disorders that have their onset during childhood and adolescence. These two critical periods of development represent sensitive time windows for environmentally induced modifications and damage to central myelin structure and functions. Here we discussed the involvement of myelin in Autism Spectrum Disorders (ASD) and schizophrenia, two major NNDs characterized by overlapping symptoms such as communication difficulties and social withdrawal.

Autism Spectrum Disorders

As a classic example of NDD etiology, consisting of a mix of genetic and environmental risk factors, an accumulating body of evidence demonstrates that myelin deficits underlie altered communication between major brain hubs in ASD individuals [92]. As demonstrated by Magnetic Resonance Imaging (MRI) and Diffusion Tensor Imaging (DTI), white matter disruptions are widespread in children and adolescents with ASD [93,94,95]. Intriguingly, the white matter of autistic patients is overgrown during the first two years of life, but tends to be smaller than controls as they age [96]. These observations in humans were recently confirmed and termed “precocious myelination” in a murine model of ASD (BTBR mice) in which the number of OLs and myelin content in the frontal brain of neonatal pups was increased [97]. This accelerated postnatal development of the brain in ASD patients that tends to normalize and worsen with age might be more nuanced for gray matter myelination. It has been shown using T1w and T2w MRI that the overall spatial patterns of intracortical myelin distribution are similar between ASD children between 1.5 and 5.5 years compared to typically developing children, but that the age-related increase in intracortical myelination is impaired in ASD [98]. At the cellular level, OPCs cultured from a mouse model of ASD (Ptenm3m4) have an enhanced proliferation rate and a premature maturation onto OLs [99]. This maturation defect does not lead in vivo to a greater number of OLs in the adult, as these cells die by apoptosis and produce abnormal myelin which fails to ensheath axons [99]. In another mouse model of ASD induced by the prenatal exposure to valproic acid, OL density and myelin content is decreased in adult mice in some of the main brain regions linked to social behavior, such as mPFC, pyriform cortex and basolateral amygdala [100]. Integrated transcriptomic analyses of both ASD mouse models and ASD patients tissues further stress OL gene dysregulation and myelination defects across species, as a highlight in both syndromic and idiopathic ASD [101,102]. Another area of interest concerns myelin proteins such as MBP, that has been put forward as targeted by an abnormal autoimmune reaction in the ASD brain [103]. However, while molecular and cellular alterations in OL biology and myelination are a hallmark of ASD, it is unknown whether these are responsible for social behavior deficits in the disease. Interestingly, frontal cortex myelin thickness reduction has been associated with a murine model of Williams syndrome (WS), a non-canonical NDD characterized by hypersociability [104], proving that conflicting behaviors, hypersociability in WS vs hyposociability in ASD, can arise from similar myelin abnormalities (hypomyelination), further stressing the complex etiology and symptomatology of such diseases.
These studies in ASD have singled out myelin and myelinating cells as potential therapeutical targets in a few preclinical studies. Promyelinating compounds such as clemastine -which promotes OPC differentiation into OLs and has been studied as a promyelinating agent in other myelin-related disorders such multiple sclerosis [105]- appear to rescue the cellular, structural and behavioral phenotype of the ASD mouse model of Pitt-Hopkins syndrome [106], opening new and exciting areas of investigation for future therapies. Furthermore, in a mouse model of perinatal hypoxia (a condition commonly associated with ASD in humans), which exhibits significant myelination impairments, early environmental enrichment was also shown to selectively promote endogenous myelin regeneration and functional recovery in the developing white matter [107]. Therefore, an alternative therapeutic strategy to improve myelination and whithe matter dysfunction might be the early behavioral intervention and environmental enrichment.

Schizophrenia

Schizophrenia (SCZ) onset coincides with adolescence and early adulthood, but its origins can be traced back to earlier stages of development as some cognitive impairments, depression and negative symptoms can occur during childhood [108]. Many evidence suggest that myelin alterations are as prevalent in this disease as they are in ASD. Although the neurobiological mechanisms underlying SCZ are not fully understood, it has been proposed that genetic and environmental risk factors during the perinatal period, either in utero or in infancy, contributes to neurodevelopmental abnormalities that may lead to impaired myelination in the adult brain [109]. The use of myelinating cells and myelin as a prism to look at this disorder is compelling because myelination is a protracted developmental process in most of the brain regions found to be dysfunctional in SCZ [109,110]. Myelination impairments during development have been considered to result in a defective maturation of neuronal networks connectivity (the ‘dysconnectivity’ hypothesis), which could explain some of the varying cognitive symptoms in SCZ patients, including cognitive flexibility [111,112,113,114]. Similarly to ASD, imaging studies questioning the structural integrity of white matter and the inter-connectivity of various brain regions have provided a better understanding of structural insults in SCZ patients [110]. Although most of the metrics used in imaging can be related to various structural components of white matter (axon diameter, fiber density, myelination), foundational work investigating both total and frontal white matter regions suggested an overall hypomyelination of the corpus callosum in human SCZ patients [115]. These findings were corroborated by post-mortem analyses of the anterior frontal cortex which showed a reduction in the expression of the two OL-associated proteins, MAG and CNPase, in SCZ patients [115]. It was subsequently observed that frontal white matter is indeed recurrently defective in chronic patients [116,117,118]. On the other hand, a recent study focusing on gray matter highlight more complex changes with some regions exhibiting higher and others lower myelin content in first-episode treatment-naïve SCZ patients [119].
Recent genetic, epigenetic and biochemical analyses have corroborated OL dysfunction and abnormal expression of myelin-related genes and proteins [120,121] as well as a decrease in the density of OLs in layer V of the PFC in SCZ patients [122]. As compared to normal OPC numbers, a reduction in OL density hints at a differentiation impairment of OPCs in the PFC of these patients [123]. Moreover, SCZ-like behaviors in juvenile mice such as impaired sociability can be elicited via a DNA hypermethylation, a hallmark risk factor of SCZ, that targets genes related to the OL lineage cells [124]. Overall, dysfunctional OL lineage cells could explain, to some extent, myelination insult of SCZ patients although many questions remain as to the origins of such disorders and their temporal unfolding, ultimately asking if dysmyelination is a cause or a result of SCZ [109,117]. An important point of discord from human studies is the difficulty of untangling the mesh of possible myelin insults as studies include a heterogenous population of patients: chronic patients that have been medicated for years, first episode patients naïve for any treatment, high risk patients, familial genetic risk patients. They are usually age and gender matched with the controls but might still account for slight contradictory results. A standardisation of patient cohorts is needed to confirm previous results and produce finer insight in the investigations. Although further research is needed on this regard, a recent report demonstrated that specific mutations in chondroitin sulfate proteoglycan 4 (CSPG4/NG2), a hallmark protein of OPCs exhibited familial segregation in SCZ patients having significant abnormal white matter integrity [125], a finding in favor of a direct role of OL lineage cells in this disease.
All these studies suggest the function of myelin connecting functional hubs for the synchronization of distant neuronal ensembles and optimal behavioral responses to a changing environment. Brain connectivity analyses indeed indicate that long-range connectivity is usually impaired in SCZ. Along with white matter integrity impairments, another substantial evidence supports a causal role of local GABAergic interneuron dysfunction in linking cortical circuit and behavioral deficits in this disease [85]. Several reports have found that alterations in local oscillations, mainly gamma oscillations, occur during performance of cognitive control tasks [85,126,127]. As previously mentioned, synchronization of cortical networks in the gamma band frequency is highly dependent on the activity of PV interneurons, which provide robust perisomatic inhibitory control of excitatory neurons [128,129]. This probably explains why dysfunctions in PV interneuron and gamma oscillations have been associated with cognitive deficits characteristic of SCZ [85,130,131]. Interestingly, myelination defects occurred specifically in PV interneurons of the mPFC in a rat model displaying schizophrenia-like behaviors [132]. Considering these findings, the high levels of myelination of PV interneurons and the early and reciprocal interactions between cortical PV interneurons and OPCs, it might be possible that impairments in PV interneuron myelination compromise the integrity of precisely timed action potentials and local synchronization [133,134]. An interesting line of study in the field of myelin will be to investigate whether PV interneuron and OL lineage abnormalities can synergize to increase the risk of developing NDDs.
As for ASD, myelination could be a potential biological target for SCZ. In this line, pro-myelinating drugs could be evaluated, for example, as precognitive interventions in first-episode patients. Antipsychotic drugs that could act on OL dysfunction by potentiating their differentiation and maturation, such as the NMDA receptor ligand D-serine, and lithium [135] are another area of excitement in terms of SCZ treatment, just like we previously discussed with promyelinating compounds as possible therapies for ASD.

Authors Contributions

All authors contributed to the conception of the article and wrote the manuscript.

Ethics Approval

No experimental data requiring approval is presented.

Consent for Publication

All authors have given consent for publication.

Availability of Data and Material

No data presented.

Competing Interests

The authors have declared that no competing interests exist.

Funding

This work was supported by grants Fondation pour la Recherche Médicale (FRM, EQU202103012626), ANR CoLD (ANR, ANR-20-CE16–0001-01) and ANR Myelex (ANR, ANR-21-CE37–0020). M.C.A. is a CNRS (Centre National de la Recherche Scientifique) investigator.

References

  1. Kessaris N, Fogarty M, Iannarelli P, et al (Feb) Competing waves of oligodendrocytes in the forebrain and postnatal elimination of an embryonic lineage. Nat Neurosci 9:173–9. [CrossRef]
  2. Bergles DE, Richardson WD (2016) Oligodendrocyte Development and Plasticity. Cold Spring Harb Perspect Biol 8:a020453. [CrossRef]
  3. Rivers LE, Young KM, Rizzi M, et al (Dec) PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice. Nat Neurosci 11:1392–401.
  4. Dimou L, Simon C, Kirchhoff F, et al (Oct 8) Progeny of Olig2-expressing progenitors in the gray and white matter of the adult mouse cerebral cortex. J Neurosci 28:10434–10442.
  5. Franklin RJM, Goldman SA (2015) Glia Disease and Repair—Remyelination. Cold Spring Harb Perspect Biol 7:a020594. [CrossRef]
  6. Cristobal CD, Lee HK (2022) Development of myelinating glia: An overview. Glia 70:2237–2259. [CrossRef]
  7. Chapman TW, Olveda GE, Bame X, et al (2023) Oligodendrocyte death initiates synchronous remyelination to restore cortical myelin patterns in mice. Nat Neurosci 26:555–569. [CrossRef]
  8. Đặng TC, Ishii Y, Nguyen VD, et al (2019) Powerful Homeostatic Control of Oligodendroglial Lineage by PDGFRα in Adult Brain. Cell Reports 27:1073-1089.e5. [CrossRef]
  9. Zhu X, Hill RA, Dietrich D, et al (Feb) Age-dependent fate and lineage restriction of single NG2 cells. Development 138:745–53. [CrossRef]
  10. Xiao Y, Czopka T (2023) Myelination-independent functions of oligodendrocyte precursor cells in health and disease. Nat Neurosci 26:1663–1669. [CrossRef]
  11. Saab AS, Nave K-A (2017) Myelin dynamics: protecting and shaping neuronal functions. Curr Opin Neurobiol 47:104–112. [CrossRef]
  12. Moore S, Meschkat M, Ruhwedel T, et al (2020) A role of oligodendrocytes in information processing. Nat Commun 11:5497. [CrossRef]
  13. Hughes AN (2021) Glial Cells Promote Myelin Formation and Elimination. Front Cell Dev Biol 9:661486. [CrossRef]
  14. Nave K-A, Asadollahi E, Sasmita A (2023) Expanding the function of oligodendrocytes to brain energy metabolism. Curr Opin Neurobiol 83:102782. [CrossRef]
  15. Simons M, Nave K-A (2015) Oligodendrocytes: Myelination and Axonal Support. Cold Spring Harb Perspect Biol 8:a020479. [CrossRef]
  16. Stadelmann C, Timmler S, Barrantes-Freer A, Simons M (2019) Myelin in the Central Nervous System: Structure, Function, and Pathology. Physiol Rev 99:1381–1431. [CrossRef]
  17. Rasband MN, Peles E (2021) Mechanisms of node of Ranvier assembly. Nat Rev Neurosci 22:7–20. [CrossRef]
  18. Ffrench-Constant C, Miller RH, Kruse J, et al (1986) Molecular specialization of astrocyte processes at nodes of Ranvier in rat optic nerve. The Journal of cell biology 102:844–852. [CrossRef]
  19. Lezmy J, Arancibia-Cárcamo IL, Quintela-López T, et al (2021) Astrocyte Ca 2+ -evoked ATP release regulates myelinated axon excitability and conduction speed. Science 374:eabh2858. [CrossRef]
  20. Serwanski DR, Jukkola P, Nishiyama A (2017) Heterogeneity of astrocyte and NG2 cell insertion at the node of ranvier. J Comp Neurol 525:535–552. [CrossRef]
  21. Ronzano R, Roux T, Thetiot M, et al (2021) Microglia-neuron interaction at nodes of Ranvier depends on neuronal activity through potassium release and contributes to remyelination. Nat Commun 12:5219. [CrossRef]
  22. Zhang J, Yang X, Zhou Y, et al (2019) Direct contacts of microglia on myelin sheath and Ranvier’s node in the corpus callosum in rats. J Biomed Res 33:192. [CrossRef]
  23. Ishibashi T, Baba H (2022) Paranodal Axoglial Junctions, an Essential Component in Axonal Homeostasis. Front Cell Dev Biol 10:951809. [CrossRef]
  24. Tasaki I (1939) THE ELECTRO-SALTATORY TRANSMISSION OF THE NERVE IMPULSE AND THE EFFECT OF NARCOSIS UPON THE NERVE FIBER. American Journal of Physiology-Legacy Content 127:211–227. [CrossRef]
  25. Huxley AF, Stämpfli R (1949) Evidence for saltatory conduction in peripheral myelinated nerve fibres. J Physiol 108:315–339.
  26. Freeman SA, Desmazières A, Fricker D, et al (2016) Mechanisms of sodium channel clustering and its influence on axonal impulse conduction. Cell Mol Life Sci 73:723–735. [CrossRef]
  27. Amor V, Zhang C, Vainshtein A, et al (2017) The paranodal cytoskeleton clusters Na+ channels at nodes of Ranvier. eLife 6:e21392. [CrossRef]
  28. Devaux J, Alcaraz G, Grinspan J, et al (2003) Kv3.1b Is a Novel Component of CNS Nodes. J Neurosci 23:4509–4518. [CrossRef]
  29. Devaux JJ, Kleopa KA, Cooper EC, Scherer SS (2004) KCNQ2 Is a Nodal K + Channel. J Neurosci 24:1236–1244. [CrossRef]
  30. Kanda H, Ling J, Tonomura S, et al (2019) TREK-1 and TRAAK Are Principal K+ Channels at the Nodes of Ranvier for Rapid Action Potential Conduction on Mammalian Myelinated Afferent Nerves. Neuron 104:960-971.e7. [CrossRef]
  31. Kozar-Gillan N, Velichkova A, Kanatouris G, et al (2023) LGI3/2–ADAM23 interactions cluster Kv1 channels in myelinated axons to regulate refractory period. Journal of Cell Biology 222:e202211031. [CrossRef]
  32. Pinatel D, Faivre-Sarrailh C (2020) Assembly and Function of the Juxtaparanodal Kv1 Complex in Health and Disease. Life 11:8. [CrossRef]
  33. Larson VA, Mironova Y, Vanderpool KG, et al (2018) Oligodendrocytes control potassium accumulation in white matter and seizure susceptibility. eLife 7:e34829. [CrossRef]
  34. Cohen CCH, Popovic MA, Klooster J, et al (2020) Saltatory Conduction along Myelinated Axons Involves a Periaxonal Nanocircuit. Cell 180:311-322.e15. [CrossRef]
  35. Fünfschilling U, Supplie LM, Mahad D, et al (2012) Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 485:517–521. [CrossRef]
  36. Lee Y, Morrison BM, Li Y, et al (2012) Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487:443–448. [CrossRef]
  37. Micu I, Jiang Q, Coderre E, et al (Feb 23) NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia. Nature 439:988–92. [CrossRef]
  38. Saab AS, Tzvetavona ID, Trevisiol A, et al (2016) Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism. Neuron 91:119–132. [CrossRef]
  39. Frühbeis C, Fröhlich D, Kuo WP, et al (2013) Neurotransmitter-Triggered Transfer of Exosomes Mediates Oligodendrocyte–Neuron Communication. PLoS Biol 11:e1001604. [CrossRef]
  40. Mukherjee C, Kling T, Russo B, et al (2020) Oligodendrocytes Provide Antioxidant Defense Function for Neurons by Secreting Ferritin Heavy Chain. Cell Metabolism 32:259-272.e10. [CrossRef]
  41. Ibrahim M, Butt AM, Berry M (1995) Relationship between myelin sheath diameter and internodal length in axons of the anterior medullary velum of the adult rat. J Neurol Sci 133:119–127. [CrossRef]
  42. Mayoral SR, Etxeberria A, Shen Y-AA, Chan JR (2018) Initiation of CNS Myelination in the Optic Nerve Is Dependent on Axon Caliber. Cell Rep 25:544-550.e3. [CrossRef]
  43. Bechler ME, Byrne L, Ffrench-Constant C (2015) CNS Myelin Sheath Lengths Are an Intrinsic Property of Oligodendrocytes. Curr Biol 25:2411–2416. [CrossRef]
  44. Gibson EM, Purger D, Mount CW, et al (May 2) Neuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain. Science 344:1252304. 2 May. [CrossRef]
  45. Tomassy GS, Berger DR, Chen H-H, et al (2014) Distinct profiles of myelin distribution along single axons of pyramidal neurons in the neocortex. Science 344:319–324. [CrossRef]
  46. Micheva KD, Wolman D, Mensh BD, et al (2016) A large fraction of neocortical myelin ensheathes axons of local inhibitory neurons. eLife 5:e15784. [CrossRef]
  47. Stedehouder J, Couey J, Brizee D, et al (2017) Fast-spiking Parvalbumin Interneurons are Frequently Myelinated in the Cerebral Cortex of Mice and Humans. Cereb Cortex 27:5001–5013.
  48. Balia M, Benamer N, Angulo MC (2017) A specific GABAergic synapse onto oligodendrocyte precursors does not regulate cortical oligodendrogenesis. Glia 65:1821–1832. [CrossRef]
  49. Stedehouder J, Brizee D, Slotman JA, et al (2019) Local axonal morphology guides the topography of interneuron myelination in mouse and human neocortex. eLife 8:. [CrossRef]
  50. Benamer N, Vidal M, Balia M, Angulo MC (2020) Myelination of parvalbumin interneurons shapes the function of cortical sensory inhibitory circuits. Nat Commun 11:5151. [CrossRef]
  51. Hijazi S, Pascual-García M, Nabawi Y, Kushner SA (2023) A critical period for prefrontal cortex PV interneuron myelination and maturation. Neuroscience.
  52. Kole K, Voesenek BJB, Brinia ME, et al (2022) Parvalbumin basket cell myelination accumulates axonal mitochondria to internodes. Nat Commun 13:7598. [CrossRef]
  53. Timmler S, Simons M (2019) Grey matter myelination. Glia 67:2063–2070. [CrossRef]
  54. De Faria O, Pivonkova H, Varga B, et al (2021) Periods of synchronized myelin changes shape brain function and plasticity. Nat Neurosci 24:1508–1521. [CrossRef]
  55. Sowell ER, Thompson PM, Holmes CJ, et al (1999) In vivo evidence for post-adolescent brain maturation in frontal and striatal regions. Nat Neurosci 2:859–861. [CrossRef]
  56. Miller DJ, Duka T, Stimpson CD, et al (2012) Prolonged myelination in human neocortical evolution. Proc Natl Acad Sci USA 109:16480–16485. [CrossRef]
  57. Dubois J, Dehaene-Lambertz G, Kulikova S, et al (2014) The early development of brain white matter: A review of imaging studies in fetuses, newborns and infants. Neuroscience 276:48–71. [CrossRef]
  58. Ueda S, Niwa M, Hioki H, et al (2015) Sequence of Molecular Events during the Maturation of the Developing Mouse Prefrontal Cortex. Complex Psychiatry 1:94–104. [CrossRef]
  59. Piredda GF, Hilbert T, Thiran J, Kober T (2021) Probing myelin content of the human brain with MRI: A review. Magnetic Resonance in Med 85:627–652. [CrossRef]
  60. Grotheer M, Rosenke M, Wu H, et al (2022) White matter myelination during early infancy is linked to spatial gradients and myelin content at birth. Nat Commun 13:997. [CrossRef]
  61. Kaller MS, Lazari A, Blanco-Duque C, et al (2017) Myelin plasticity and behaviour-connecting the dots. Curr Opin Neurobiol 47:86–92. [CrossRef]
  62. Genc S, Raven EP, Drakesmith M, et al (2023) Novel insights into axon diameter and myelin content in late childhood and adolescence. Cereb Cortex 33:6435–6448. [CrossRef]
  63. Lebel C, Deoni S (2018) The development of brain white matter microstructure. NeuroImage 182:207–218. [CrossRef]
  64. Nagy B, Hovhannisyan A, Barzan R, et al (2017) Different patterns of neuronal activity trigger distinct responses of oligodendrocyte precursor cells in the corpus callosum. PLoS Biol 15:e2001993. [CrossRef]
  65. Makinodan M, Rosen KM, Ito S, Corfas G (2012) A critical period for social experience-dependent oligodendrocyte maturation and myelination. Science 337:1357–1360. [CrossRef]
  66. Vélez-Fort M, Maldonado PP, Butt AM, et al (May 19) Postnatal switch from synaptic to extrasynaptic transmission between interneurons and NG2 cells. J Neurosci 30:6921–6929. 19 May. [CrossRef]
  67. Orduz D, Maldonado PP, Balia M, et al (2015) Interneurons and oligodendrocyte progenitors form a structured synaptic network in the developing neocortex. eLife 4:e06953. [CrossRef]
  68. Fang L-P, Zhao N, Caudal LC, et al (2022) Impaired bidirectional communication between interneurons and oligodendrocyte precursor cells affects social cognitive behavior. Nat Commun 13:1394. [CrossRef]
  69. McKenzie IA, Ohayon D, Li H, et al (2014) Motor skill learning requires active central myelination. Science 346:318–322. [CrossRef]
  70. Hughes EG, Orthmann-Murphy JL, Langseth AJ, Bergles DE (2018) Myelin remodeling through experience-dependent oligodendrogenesis in the adult somatosensory cortex. Nat Neurosci 21:696–706. [CrossRef]
  71. Hill RA, Li AM, Grutzendler J (2018) Lifelong cortical myelin plasticity and age-related degeneration in the live mammalian brain. Nat Neurosci 21:683–695. [CrossRef]
  72. Munyeshyaka M, Fields RD (2022) Oligodendroglia are emerging players in several forms of learning and memory. Commun Biol 5:1148. [CrossRef]
  73. Bacmeister CM, Huang R, Osso LA, et al (2022) Motor learning drives dynamic patterns of intermittent myelination on learning-activated axons. Nat Neurosci 25:1300–1313. [CrossRef]
  74. Ortiz FC, Habermarcher C, Graciarena M, et al (2019) Neuronal activity in vivo enhances functional myelin repair. JCI Insight 4:e123434.
  75. Teissier A, Le Magueresse C, Olusakin J, et al (2020) Early-life stress impairs postnatal oligodendrogenesis and adult emotional behaviour through activity-dependent mechanisms. Mol Psychiatry 25:1159–1174. [CrossRef]
  76. Makinodan M, Ikawa D, Yamamuro K, et al (2017) Effects of the mode of re-socialization after juvenile social isolation on medial prefrontal cortex myelination and function. Sci Rep 7:5481. [CrossRef]
  77. Liu J, Dietz K, DeLoyht JM, et al (2012) Impaired adult myelination in the prefrontal cortex of socially isolated mice. Nat Neurosci 15:1621–1623. [CrossRef]
  78. Steadman PE, Xia F, Ahmed M, et al (2020) Disruption of Oligodendrogenesis Impairs Memory Consolidation in Adult Mice. Neuron 105:150-164.e6. [CrossRef]
  79. Shimizu T, Nayar SG, Swire M, et al (2023) Oligodendrocyte dynamics dictate cognitive performance outcomes of working memory training in mice. Nat Commun 14:6499. [CrossRef]
  80. Pan S, Mayoral SR, Choi HS, et al (2020) Preservation of a remote fear memory requires new myelin formation. Nat Neurosci 23:487–499. [CrossRef]
  81. Barron T, Saifetiarova J, Bhat MA, Kim JH (2018) Myelination of Purkinje axons is critical for resilient synaptic transmission in the deep cerebellar nucleus. Sci Rep 8:1022. [CrossRef]
  82. Dubey M, Pascual-Garcia M, Helmes K, et al (2022) Myelination synchronizes cortical oscillations by consolidating parvalbumin-mediated phasic inhibition. Elife 11:e73827. [CrossRef]
  83. Cullen CL, Pepper RE, Clutterbuck MT, et al (2021) Periaxonal and nodal plasticities modulate action potential conduction in the adult mouse brain. Cell Reports 34:108641. [CrossRef]
  84. Buzsáki G, Anastassiou CA, Koch C (2012) The origin of extracellular fields and currents — EEG, ECoG, LFP and spikes. Nat Rev Neurosci 13:407–420. [CrossRef]
  85. Spellman TJ, Gordon JA (2015) Synchrony in schizophrenia: a window into circuit-level pathophysiology. Curr Opin Neurobiol 30:17–23. [CrossRef]
  86. Jung F, Carlén M (2021) Neuronal oscillations and the mouse prefrontal cortex. In: International Review of Neurobiology. Elsevier, pp 337–372.
  87. Bragin A, Jando G, Nadasdy Z, et al (1995) Gamma (40-100 Hz) oscillation in the hippocampus of the behaving rat. J Neurosci 15:47–60. [CrossRef]
  88. Fujisawa S, Buzsáki G (2011) A 4 Hz oscillation adaptively synchronizes prefrontal, VTA, and hippocampal activities. Neuron 72:153–165. [CrossRef]
  89. Hunt BAE, Tewarie PK, Mougin OE, et al (2016) Relationships between cortical myeloarchitecture and electrophysiological networks. PNAS 113:13510–13515. [CrossRef]
  90. Pajevic S, Basser PJ, Fields RD (2014) Role of myelin plasticity in oscillations and synchrony of neuronal activity. Neuroscience 276:135–147. [CrossRef]
  91. Pajevic S, Plenz D, Basser PJ, Fields RD (2023) Oligodendrocyte-mediated myelin plasticity and its role in neural synchronization. Elife 12:e81982. [CrossRef]
  92. Travers BG, Adluru N, Ennis C, et al (2012) Diffusion tensor imaging in autism spectrum disorder: a review. Autism Res 5:289–313. [CrossRef]
  93. Frazier TW, Youngstrom EA, Sinclair L, et al (2010) Autism spectrum disorders as a qualitatively distinct category from typical behavior in a large, clinically ascertained sample. Assessment 17:308–320. [CrossRef]
  94. Ameis SH, Lerch JP, Taylor MJ, et al (2016) A Diffusion Tensor Imaging Study in Children With ADHD, Autism Spectrum Disorder, OCD, and Matched Controls: Distinct and Non-Distinct White Matter Disruption and Dimensional Brain-Behavior Relationships. Am J Psychiatry 173:1213–1222. [CrossRef]
  95. Shukla DK, Keehn B, Smylie DM, Müller R-A (2011) Microstructural abnormalities of short-distance white matter tracts in autism spectrum disorder. Neuropsychologia 49:1378–1382. [CrossRef]
  96. Wolff JJ, Gerig G, Lewis JD, et al (2015) Altered corpus callosum morphology associated with autism over the first 2 years of life. Brain 138:2046–2058. [CrossRef]
  97. Khanbabaei M, Hughes E, Ellegood J, et al (2019) Precocious myelination in a mouse model of autism. Transl Psychiatry 9:251. [CrossRef]
  98. Chen B, Linke A, Olson L, et al (2022) Cortical myelination in toddlers and preschoolers with autism spectrum disorder. Dev Neurobiol 82:261–274. [CrossRef]
  99. Lee H, Thacker S, Sarn N, et al (2019) Constitutional mislocalization of Pten drives precocious maturation in oligodendrocytes and aberrant myelination in model of autism spectrum disorder. Transl Psychiatry 9:13. [CrossRef]
  100. Graciarena M, Seiffe A, Nait-Oumesmar B, Depino AM (2018) Hypomyelination and Oligodendroglial Alterations in a Mouse Model of Autism Spectrum Disorder. Front Cell Neurosci 12:517. [CrossRef]
  101. Richetto J, Chesters R, Cattaneo A, et al (2016) Genome-Wide Transcriptional Profiling and Structural Magnetic Resonance Imaging in the Maternal Immune Activation Model of Neurodevelopmental Disorders. Cereb Cortex cercor;bhw320v1. [CrossRef]
  102. Phan BN, Bohlen JF, Davis BA, et al (2020) A myelin-related transcriptomic profile is shared by Pitt–Hopkins syndrome models and human autism spectrum disorder. Nat Neurosci 23:375–385. [CrossRef]
  103. Robinson-Agramonte MDLA, Noris García E, Fraga Guerra J, et al (2022) Immune Dysregulation in Autism Spectrum Disorder: What Do We Know about It? IJMS 23:3033. [CrossRef]
  104. Barak B, Zhang Z, Liu Y, et al (2019) Neuronal deletion of Gtf2i, associated with Williams syndrome, causes behavioral and myelin alterations rescuable by a remyelinating drug. Nat Neurosci 22:700–708. [CrossRef]
  105. Green AJ, Gelfand JM, Cree BA, et al (2017) Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet 390:2481–2489. [CrossRef]
  106. Bohlen JF, Cleary CM, Das D, et al (2023) Promyelinating drugs promote functional recovery in an autism spectrum disorder mouse model of Pitt-Hopkins syndrome. Brain 146:3331–3346. [CrossRef]
  107. Forbes TA, Goldstein EZ, Dupree JL, et al (2020) Environmental enrichment ameliorates perinatal brain injury and promotes functional white matter recovery. Nat Commun 11:964. [CrossRef]
  108. Sakurai T, Gamo NJ (2019) Cognitive functions associated with developing prefrontal cortex during adolescence and developmental neuropsychiatric disorders. Neurobiology of Disease 131:104322. [CrossRef]
  109. Fessel J (2022) Abnormal oligodendrocyte function in schizophrenia explains the long latent interval in some patients. Transl Psychiatry 12:120. [CrossRef]
  110. Fields RD (Jul) White matter in learning, cognition and psychiatric disorders. Trends Neurosci 31:361–70. [CrossRef]
  111. Friston KJ, Frith CD (1995) Schizophrenia: a disconnection syndrome? Clin Neurosci 3:89–97.
  112. Dwork AJ, Mancevski B, Rosoklija G (2007) White matter and cognitive function in schizophrenia. The international journal of neuropsychopharmacology 10:513–536. [CrossRef]
  113. Voineskos AN, Lobaugh NJ, Bouix S, et al (2010) Diffusion tensor tractography findings in schizophrenia across the adult lifespan. Brain 133:1494–1504. [CrossRef]
  114. Valdés-Tovar M, Rodríguez-Ramírez AM, Rodríguez-Cárdenas L, et al (2022) Insights into myelin dysfunction in schizophrenia and bipolar disorder. World J Psychiatry 12:264–285. [CrossRef]
  115. Flynn SW, Lang DJ, Mackay AL, et al (2003) Abnormalities of myelination in schizophrenia detected in vivo with MRI, and post-mortem with analysis of oligodendrocyte proteins. Mol Psychiatry 8:811–820. [CrossRef]
  116. Palaniyappan L, Al-Radaideh A, Mougin O, et al (2013) Combined White Matter Imaging Suggests Myelination Defects in Visual Processing Regions in Schizophrenia. Neuropsychopharmacol 38:1808–1815. [CrossRef]
  117. Wheeler AL, Voineskos AN (2014) A review of structural neuroimaging in schizophrenia: from connectivity to connectomics. Front Hum Neurosci 8:. [CrossRef]
  118. Maas DA, Vallès A, Martens GJM (2017) Oxidative stress, prefrontal cortex hypomyelination and cognitive symptoms in schizophrenia. Transl Psychiatry 7:e1171–e1171. [CrossRef]
  119. Wei W, Poirion E, Bodini B, et al (2020) Predicting PET-derived myelin content from multisequence MRI for individual longitudinal analysis in multiple sclerosis. Neuroimage 223:117308. [CrossRef]
  120. Chen X, Duan H, Xiao L, Gan J (2018) Genetic and Epigenetic Alterations Underlie Oligodendroglia Susceptibility and White Matter Etiology in Psychiatric Disorders. Front Genet 9:565. [CrossRef]
  121. Martins-de-Souza D, Guest PC, Reis-de-Oliveira G, et al (2021) An overview of the human brain myelin proteome and differences associated with schizophrenia. World J Biol Psychiatry 22:271–287. [CrossRef]
  122. Kolomeets NS, Uranova NA (2019) Reduced oligodendrocyte density in layer 5 of the prefrontal cortex in schizophrenia. Eur Arch Psychiatry Clin Neurosci 269:379–386. [CrossRef]
  123. Mauney SA, Pietersen CY, Sonntag K-C, Woo T-UW (2015) Differentiation of oligodendrocyte precursors is impaired in the prefrontal cortex in schizophrenia. Schizophr Res 169:374–380. [CrossRef]
  124. Chen X, Huang N-X, Cheng Y-J, et al (2021) DNA Hypermethylation Induced by L-Methionine Leads to Oligodendroglial and Myelin Deficits and Schizophrenia-Like Behaviors in Adolescent Mice. Front Neurosci 15:659853. [CrossRef]
  125. de Vrij FM, Bouwkamp CG, Gunhanlar N, et al (2018) Candidate CSPG4 mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia. [CrossRef]
  126. Cho RY, Konecky RO, Carter CS (2006) Impairments in frontal cortical gamma synchrony and cognitive control in schizophrenia. Proc Natl Acad Sci U S A 103:19878–19883. [CrossRef]
  127. Minzenberg MJ, Firl AJ, Yoon JH, et al (2010) Gamma oscillatory power is impaired during cognitive control independent of medication status in first-episode schizophrenia. Neuropsychopharmacology 35:2590–2599. [CrossRef]
  128. Sohal VS, Zhang F, Yizhar O, Deisseroth K (2009) Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature 459:698–702. [CrossRef]
  129. Cardin JA, Carlén M, Meletis K, et al (2009) Driving fast-spiking cells induces gamma rhythm and controls sensory responses. Nature 459:663–667. [CrossRef]
  130. Lewis DA, Hashimoto T, Volk DW (Apr) Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 6:312–24. [CrossRef]
  131. Catts VS, Fung SJ, Long LE, et al (2013) Rethinking schizophrenia in the context of normal neurodevelopment. Front Cell Neurosci 7:60. [CrossRef]
  132. Maas DA, Eijsink VD, Spoelder M, et al (2020) Interneuron hypomyelination is associated with cognitive inflexibility in a rat model of schizophrenia. Nat Commun 11:2329. [CrossRef]
  133. Stedehouder J, Kushner SA (2017) Myelination of parvalbumin interneurons: a parsimonious locus of pathophysiological convergence in schizophrenia. Mol Psychiatry 22:4–12. [CrossRef]
  134. Benamer N, Vidal M, Angulo MC (2020) The cerebral cortex is a substrate of multiple interactions between GABAergic interneurons and oligodendrocyte lineage cells. Neurosci Lett 715:134615. [CrossRef]
  135. Gouvêa-Junqueira D, Falvella ACB, Antunes ASLM, et al (2020) Novel Treatment Strategies Targeting Myelin and Oligodendrocyte Dysfunction in Schizophrenia. Front Psychiatry 11:379. [CrossRef]
Preprints 92287 g001
Figure 1. Summary of myelination effects at cellular, network and cognitive levels. A. Myelination patterns (myelin in red) of pyramidal neurons (pyr, purple) and PV interneurons (PV, blue) are different in the cortex, probably including the mPFC (right). It has been shown that myelination can affect the excitation-inhibition balance (left, Benamer et al., 2020). However, it is unknown how myelination heterogeneity impact conduction and synaptic transmission. IL and PL: infralimbic and prelimbic regions of the mPFC; ACC: anterior cingulate. B. Myelin may adjust the synchrony between neuronal ensembles of two distant brain regions (right). The synchrony of local (intracortical) and inter-regional neuronal networks generates brain oscillations at different frequencies such as gamma and theta, respectively (left). C. Myelin appear to be important for the proper perfomance of cognitive tasks such as social interactions. Behavioral performance also highly depends on brain oscillations which, in turn, are influenced by myelination.
Figure 1. Summary of myelination effects at cellular, network and cognitive levels. A. Myelination patterns (myelin in red) of pyramidal neurons (pyr, purple) and PV interneurons (PV, blue) are different in the cortex, probably including the mPFC (right). It has been shown that myelination can affect the excitation-inhibition balance (left, Benamer et al., 2020). However, it is unknown how myelination heterogeneity impact conduction and synaptic transmission. IL and PL: infralimbic and prelimbic regions of the mPFC; ACC: anterior cingulate. B. Myelin may adjust the synchrony between neuronal ensembles of two distant brain regions (right). The synchrony of local (intracortical) and inter-regional neuronal networks generates brain oscillations at different frequencies such as gamma and theta, respectively (left). C. Myelin appear to be important for the proper perfomance of cognitive tasks such as social interactions. Behavioral performance also highly depends on brain oscillations which, in turn, are influenced by myelination.
Preprints 92287 g001
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.
Prerpints.org logo

Preprints.org is a free preprint server supported by MDPI in Basel, Switzerland.

facebook logotwitter logolinkedin logo
MDPI Initiatives
Important Links
Subscribe

Disclaimer

Terms of Use

Privacy Policy

© 2024 MDPI (Basel, Switzerland) unless otherwise stated