Neurons In White Matter Research Articles

Hidden in the white matter: Current views on interstitial white matter neurons.

The mammalian brain comprises two structurally and functionally distinct compartments: the gray matter (GM) and the white matter (WM). In humans, the WM constitutes approximately half of the brain volume, yet it remains significantly less investigated than the GM. The major cellular elements of the WM are neuronal axons and glial cells. However, the WM also contains cell bodies of the interstitial neurons, estimated to number 10 to 28 million in the adult bat brain, 67 million in Lar gibbon brain, and 450 to 670 million in the adult human brain, representing as much as 1.3%, 2.25%, and 3.5% of all neurons in the cerebral cortex, respectively. Many studies investigated the interstitial WM neurons (IWMNs) using immunohistochemistry, and some information is available regarding their electrophysiological properties. However, the functional role of IWMNs in physiologic and pathologic conditions largely remains unknown. This review aims to provide a concise update regarding the distribution and properties of interstitial WM neurons, highlight possible functions of these cells as debated in the literature, and speculate about other possible functions of the IWMNs and their interactions with glial cells. We hope that our review will inspire new research on IWMNs, which represent an intriguing cell population in the brain.

SLC35A2 somatic variants in drug resistant epilepsy: FCD and MOGHE

De novo somatic (post-zygotic) gene mutations affecting neuroglial progenitor cell types in embryonic cerebral cortex are increasingly identified in patients with drug resistant epilepsy (DRE) associated with malformations of cortical development, in particular, focal cortical dysplasias (FCD). Somatic variants in at least 16 genes have been linked to FCD type II, all encoding components of the mechanistic target of rapamycin (mTOR) pathway. FCD type II is characterized histopathologically by cytomegalic dysmorphic neurons and balloon cells. In contrast, the molecular pathogenesis of FCD I subtypes is less well understood, and histological features are characterized by alterations in columnar or laminar organization without cytomegalic dysmorphic neurons or balloon cells. In 2018, we reported somatic mutations in Solute Carrier Family 35 member A2 (SLC35A2) linked to DRE underlying FCD type I and subsequently to a new histopathological phenotype: excess oligodendrocytes and heterotopic neurons in subcortical white matter known as MOGHE (mild malformation of cortical development with oligodendroglial hyperplasia). These discoveries opened the door to studies linking somatic mutations to FCD. In this review, we discuss the biology of SLC35A2 somatic mutations in epilepsy in FCD and MOGHE, and insights into SLC35A2 epilepsy pathogenesis, describing progress to date and critical areas for investigation.

Effects of Fisetin Treatment on Cellular Senescence of Various Tissues and Organs of Old Sheep.

Fisetin has been shown to be beneficial for brain injury and age-related brain disease via different mechanisms. The purpose of this study was to determine the presence of senescent cells and the effects of fisetin on cellular senescence in the brain and other vital organs in old sheep, a more translational model. Female sheep 6-7 years old (N = 6) were treated with 100 mg/kg fisetin or vehicle alone on two consecutive days a week for 8 weeks. All vital organs were harvested at the time of sacrifice. Histology, immunofluorescence staining, and RT-Q-PCR were performed on different regions of brain tissues and other organs. Our results indicated that fisetin treatment at the current regimen did not affect the general morphology of the brain. The presence of senescent cells in both the cerebral brain cortex and cerebellum and non-Cornu Ammonis (CA) area of the hippocampus was detected by senescent-associated β-galactosidase (SA-β-Gal) staining and GL13 (lipofuscin) staining. The senescent cells detected were mainly neurons in both gray and white matter of either the cerebral brain cortex, cerebellum, or non-CA area of the hippocampus. Very few senescent cells were detected in the neurons of the CA1-4 area of the hippocampus, as revealed by GL13 staining and GLB1 colocalization with NEUN. Fisetin treatment significantly decreased the number of SA-β-Gal+ cells in brain cortex white matter and GL13+ cells in the non-CA area of the hippocampus, and showed a decreasing trend of SA-β-Gal+ cells in the gray matter of both the cerebral brain cortex and cerebellum. Furthermore, fisetin treatment significantly decreased P16+ and GLB1+ cells in neuronal nuclear protein (NEUN)+ neurons, glial fibrillary acidic protein (GFAP)+ astrocytes, and ionized calcium binding adaptor molecule 1 (IBA1)+ microglia cells in both gray and white matter of cerebral brain cortex. Fisetin treatment significantly decreased GLB1+ cells in microglia cells, astrocytes, and NEUN+ neurons in the non-CA area of the hippocampus. Fisetin treatment significantly decreased plasma S100B. At the mRNA level, fisetin significantly downregulated GLB1 in the liver, showed a decreasing trend in GLB1 in the lung, heart, and spleen tissues, and significantly decreased P21 expression in the liver and lung. Fisetin treatment significantly decreased TREM2 in the lung tissues and showed a trend of downregulation in the liver, spleen, and heart. A significant decrease in NRLP3 in the liver was observed after fisetin treatment. Finally, fisetin treatment significantly downregulated SOD1 in the liver and spleen while upregulating CAT in the spleen. In conclusion, we found that senescent cells were widely present in the cerebral brain cortex and cerebellum and non-CA area of the hippocampus of old sheep. Fisetin treatment significantly decreased senescent neurons, astrocytes, and microglia in both gray and white matter of the cerebral brain cortex and non-CA area of the hippocampus. In addition, fisetin treatment decreased senescent gene expressions and inflammasomes in other organs, such as the lung and the liver. Fisetin treatment represents a promising therapeutic strategy for age-related diseases.

Shades of gray in human white matter.

Anatomists have long expressed interest in neurons of the white matter, which is by definition supposed to be free of neurons. Hypotheses regarding their biochemical signature and physiological function are mainly derived from animal models. Here, we investigated 15 whole-brain human postmortem specimens, including cognitively normal cases and those with pathologic Alzheimer's disease (AD). Quantitative and qualitative methods were used to investigate differences in neuronal size and density, and the relationship between neuronal processes and vasculature. Double staining was used to evaluate colocalization of neurochemicals. Two topographically distinct populations of neurons emerged: one appearing to arise from developmental subplate neurons and the other embedded within deep, subcortical white matter. Both populations appeared to be neurochemically heterogeneous, showing positive reactivity to acetylcholinesterase (AChE) [but not choline acetyltransferase (ChAT)], neuronal nuclei (NeuN), nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d), microtubule-associated protein 2 (MAP-2), somatostatin (SOM), nonphosphorylated neurofilament protein (SMI-32), and calcium-binding proteins calbindin-D28K (CB), calretinin (CRT), and parvalbumin (PV). PV was more richly expressed in superficial as opposed to deep white matter neurons (WMNs); subplate neurons were also significantly larger than their deeper counterparts. NADPH-d, a surrogate for nitric oxide synthase, allowed for the striking morphological visualization of subcortical WMNs. NADPH-d-positive subcortical neurons tended to embrace the outer walls of microvessels, suggesting a functional role in vasodilation. The presence of AChE positivity in these neurons, but not ChAT, suggests that they are cholinoceptive but noncholinergic. WMNs were also significantly smaller in AD compared to control cases. These observations provide a landscape for future systematic investigations.

Influence of chrysin on D-galactose induced-aging in mice: Up regulation of AMP kinase/liver kinase B1/peroxisome proliferator-activated receptor-γ coactivator 1-α signaling pathway.

Adenosine monophosphate kinase/liver kinase B1/peroxisome proliferator-activated receptor-γ coactivator 1-α (AMPK/LKB1/PGC1α) pathway has a vital role in regulating age-related diseases. It controls neurogenesis, cell proliferation, axon outgrowth, and cellular energy homeostasis. AMPK pathway also regulates mitochondrial synthesis. The current study evaluated the effect of chrysin on D-galactose (D-gal) induced-aging, neuron degeneration, mitochondrial dysfunction, oxidative stress, and neuroinflammation in mice. The mice were allocated randomly into four groups (10 each group): Group 1: normal control group, Group 2: D-gal group, Groups 3 and 4: chrysin (125 and 250 mg/kg, respectively). Groups 2-4 were injected with D-gal (200 mg/kg/day; s.c) for 8weeks to induce aging. Groups 3 and 4 were orally gavaged every day concurrent with D-gal. At the end of experiment, behavioral, brain biochemical and histopathological changes were monitored. Chrysin administration elevated discrimination ratio in object recognition, Y Maze percentage alternation, locomotor activity and brain contents of AMPK, LKB1, PGC1α, NAD (P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HO-1), nerve growth factor (NGF) (neurotrophin-3; NT-3), and seretonin as well as reduced brain contents of tumor necrosis factor-alpha (TNF-α), nuclear factor kappa B (NF-κB), advanced glycation end products (AGEs) and glial fibrillary acidic protein (GFAP) compared to D-gal-treated mice. Chrysin also alleviated cerebral cortex and white matter neurons degeneration. Chrysin protects against neurodegeneration, improves mitochondrial autophagy and biogenesis as well as activates antioxidant genes expression. In addition, chrysin ameliorates neuroinflammation and stimulates the release of NGF and serotonin neurotransmitter. So, chrysin has a neuroprotective effect in D-gal induced-aging in mice.

Cortical Layer Markers Expression and Increased Synaptic Density in Interstitial Neurons of the White Matter from Drug-Resistant Epilepsy Patients.

The interstitial neurons in the white matter of the human and non-human primate cortex share a similar developmental origin with subplate neurons and deep-layer cortical neurons. A subset of interstitial neurons expresses the molecular markers of subplate neurons, but whether interstitial neurons express cortical layer markers in the adult human brain remains unexplored. Here we report the expression of cortical layer markers in interstitial neurons in the white matter of the adult human brain, supporting the hypothesis that interstitial neurons could be derived from cortical progenitor cells. Furthermore, we found increased non-phosphorylated neurofilament protein (NPNFP) expression in interstitial neurons in the white matter of drug-resistant epilepsy patients. We also identified the expression of glutamatergic and g-aminobutyric acid (GABAergic) synaptic puncta that were distributed in the perikarya and dendrites of interstitial neurons. The density of glutamatergic and GABAergic synaptic puncta was increased in interstitial neurons in the white matter of drug-resistant epilepsy patients compared with control brain tissues with no history of epilepsy. Together, our results provide important insights of the molecular identity of interstitial neurons in the adult human white matter. Increased synaptic density of interstitial neurons could result in an imbalanced synaptic network in the white matter and participate as part of the epileptic network in drug-resistant epilepsy.

Neuropathology findings in KCNQ2 neonatal epileptic encephalopathy.

PurposeKCNQ2-epileptic encephalopathy (EE) is a neonatal epilepsy syndrome characterized by a typical clinical presentation and EEG recording, but without any brain or cortical abnormal development on MRI. Most of the patients have a severe developmental impairment. The epileptogenic mechanisms are thought to be the result of the changes of the M-current density causing a change of brain excitability. Although recent studies allow us to better understand the physiopathology of KCNQ2-EE, the neuropathology of this ion channel dysfunction has only been previously described in a single case report. MethodsWe report the neuropathology study of a case of KCNQ2-EE with a typical electro-phenotype due to a de novo heterozygous single nucleotide pathogenic variant in the exon 5 of the KCNQ2 gene (NM_172107.2:c.802C>T; p.Leu268Phe). ResultsAt the macroscopic level, the brain had a normal structure with a normal neocortical gyral pattern. At the histological level, the cortex had a usual six-layer lamination in all lobes but blurred gray-white matter boundaries due to excessive heterotopic neurons in deep white matter were observed. This diffuse mild malformation of cortical development is suggestive of a neuronal migration disorder. ConclusionIn recent years, our understanding of the role of ion channel dysfunctions in early brain development has expanded from the occurrence of EE to brain malformation. Through this rare neuropathological report, we emphasize the role of KCNQ2 channels in the process of cortical development. As for other genetic neonatal onset epilepsies, more reports are needed to further delineate the range of neuropathological abnormalities for KCNQ2-EE.

Investigation of synapses in the cortical white matter in human temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is one of the most common focal pharmacotherapy-resistant epilepsy in adults. Previous studies have shown significantly higher numbers of neurons in the neocortical white matter in TLE patients than in controls.The aim of this work was to investigate whether white matter neurons are part of the neuronal circuitry. Therefore, we studied the distribution and density of synapses in surgically resected neocortical tissue of pharmacotherapy-resistant TLE patients. Neocortical white matter of temporal lobe from non-epileptic patients were used as controls. Synapses and neurons were visualized with immunohistochemistry using antibodies against synaptophysin and NeuN, respectively. The presence of synaptophysin in presynaptic terminals was verified by electron microscopy. Quantification of immunostaining was performed and the data of the patients’ cognitive tests as well as clinical records were compared to the density of neurons and synapses.Synaptophysin density in the white matter of TLE patients was significantly higher than in controls. In TLE, a significant correlation was found between synaptophysin immunodensity and density of white matter neurons. Neuronal as well as synaptophysin density significantly correlated with scores of verbal memory of TLE patients. Neurosurgical outcome of TLE patients did not significantly correlate with histological data, although, higher neuronal and synaptophysin densities were observed in patients with favorable post-surgical outcome.Our results suggest that white matter neurons in TLE patients receive substantial synaptic input and indicate that white matter neurons may be integrated in epileptic neuronal networks responsible for the development or maintenance of seizures.

Anti-inflammatory and antioxidant effects of astaxanthin following spinal cord injury in a rat animal model

Spinal cord injury (SCI) is a severely debilitating problem leading to substantial decrease in the quality of life. After spinal cord injury, inflammation and oxidative stress plays a key role in initiating the secondary injury cascades leading to progressive tissue degradation and extreme functional deficits. Given that the primary mechanical injuries to spinal cord are rarely repaired, the pharmacological interventions may improve the neurological outcomes caused by secondary injury. Astaxanthin (AST) is considered as a xanthophyll carotenoid with potent antioxidant and anti-inflammatory properties, which has various pharmacological activities. In the present study, we aimed to firstly assess the protective effect of AST, and then to define the AST mechanism of action on a rat model of SCI. Based on the results of von Frey test, AST treatment significantly alleviated the SCI-induced neuropathic pain compared with the control groups (P < 0.05). The expression analysis by western blot shows reduced expression levels of COX-2, TNF-α, IL-1β, and IL-6 following AST treatment (P < 0.05). The activity of antioxidant enzymes was evaluated using ELISA. Therefore, ELISA experiments showed a significant reduction in the level of oxidative stress in SCI rat following AST treatment (P < 0.05). Furthermore, histopathological evaluations revealed that myelinated white matter and motor neuron number were significantly preserved after treatment with AST (P < 0.05). In conclusion, our study shows that AST could improve SCI through anti-inflammatory and antioxidant effects which leads to decreased tissue damage and mechanical pain after SCI.

The neuropathological findings of developmental and epileptic encephalopathy-43 (DEE43) and delineation of a the molecular spectrum of novel case

Developmental and epileptic encephalopathies (DEE) constitute an expanding group of severely disabling and, most frequently, drug-resistant disorders starting in the first year of life. Among them, there is DEE43, caused by dominant mutations in the GABRB3 gene. We present first neuropathological findings in a novel, molecularly confirmed case with the fatal course. The neuropathological analysis revealed co-existing developmental anomalies and retardation of myelination resulting from disturbed early brain growth as well as lesions caused by epileptic hypoxic-ischemic episodes. Developmental anomalies included misplaced neurons in the cerebellar white matter, heterotopic neurons in the cortical molecular layer and in the molecular layer of the hippocampal dentate gyrus, dysmorphic cerebellar dentate nuclei and inferior olivary nuclei in the medulla oblongata. The migrational and maturational disorders leading to the neuronal network dysfunction could be the cause of both the lack of development and the ineffectiveness of antiepileptic treatment in children affected by DEE. Giving the presented neuropathological description and based on the literature, we discuss the pathomechanism of the disease, to improve current understanding of both the lack of development and the ineffectiveness of treatment of affected children.

The distribution, number, and certain neurochemical identities of infracortical white matter neurons in the brains of a southern lesser galago, a black-capped squirrel monkey, and a crested macaque.

In the current study, we examined the number, distribution, and aspects of the neurochemical identities of infracortical white matter neurons, also termed white matter interstitial cells (WMICs), in the brains of a southern lesser galago (Galago moholi), a black-capped squirrel monkey (Saimiri boliviensis boliviensis), and a crested macaque (Macaca nigra). Staining for neuronal nuclear marker (NeuN) revealed WMICs throughout the infracortical white matter, these cells being most dense close to inner cortical border, decreasing in density with depth in the white matter. Stereological analysis of NeuN-immunopositive cells revealed estimates of approximately 1.1, 10.8, and 37.7 million WMICs within the infracortical white matter of the galago, squirrel monkey, and crested macaque, respectively. The total numbers of WMICs form a distinct negative allometric relationship with brain mass and white matter volume when examined in a larger sample of primates where similar measures have been obtained. In all three primates studied, the highest densities of WMICs were in the white matter of the frontal lobe, with the occipital lobe having the lowest. Immunostaining revealed significant subpopulations of WMICs containing neuronal nitric oxide synthase (nNOS) and calretinin, with very few WMICs containing parvalbumin, and none containing calbindin. The nNOS and calretinin immunopositive WMICs represent approximately 21% of the total WMIC population; however, variances in the proportions of these neurochemical phenotypes were noted. Our results indicate that both the squirrel monkey and crested macaque might be informative animal models for the study of WMICs in neurodegenerative and psychiatric disorders in humans.

The distribution, number, and certain neurochemical identities of infracortical white matter neurons in a chimpanzee (Pan troglodytes) brain.

We examined the number, distribution, and immunoreactivity of the infracortical white matter neuronal population, also termed white matter interstitial cells (WMICs), throughout the telencephalic white matter of an adult female chimpanzee. Staining for neuronal nuclear marker (NeuN) revealed WMICs throughout the infracortical white matter, these cells being most numerous and dense close to the inner border of cortical layer VI, decreasing significantly in density with depth in the white matter. Stereological analysis of NeuN-immunopositive cells revealed an estimate of approximately 137.2million WMICs within the infracortical white matter of the chimpanzee brain studied. Immunostaining revealed subpopulations of WMICs containing neuronal nitric oxide synthase (nNOS, approximately 14.4million in number), calretinin (CR, approximately 16.7million), very few WMICs containing parvalbumin (PV), and no calbindin-immunopositive neurons. The nNOS, CR, and PV immunopositive WMICs, possibly all inhibitory neurons, represent approximately 22.6% of the total WMIC population. As the white matter is affected in many cognitive conditions, such as schizophrenia, autism, epilepsy, and also in neurodegenerative diseases, understanding these neurons across species is important for the translation of findings of neural dysfunction in animal models to humans. Furthermore, studies of WMICs in species such as apes provide a crucial phylogenetic context for understanding the evolution of these cell types in the human brain.

Neurite Outgrowth Inhibitor (NogoA) Is Upregulated in White Matter Lesions of Complex Cortical Malformations.

Complex cortical malformations (CCMs), such as hemimegalencephaly and polymicrogyria, are associated with drug-resistant epilepsy and developmental impairment. They share certain neuropathological characteristics including mammalian target of rapamycin (mTOR) activation and an atypical number of white matter neurons. To get a better understanding of the pathobiology of the lesion architecture, we investigated the role of neurite outgrowth inhibitor A (NogoA), a known regulator of neuronal migration. Epilepsy surgery specimens from 16 CCM patients were analyzed and compared with sections of focal cortical dysplasia IIB (FCD IIB, n = 22), tuberous sclerosis complex (TSC, n = 8) as well as healthy controls (n = 15). Immunohistochemistry was used to characterize NogoA, myelination, and mTOR signaling. Digital slides were evaluated automatically with ImageJ. NogoA staining showed a significantly higher expression within the white matter of CCM and FCD IIB, whereas cortical tubers presented levels similar to controls. Further analysis of possible associations of NogoA with other factors revealed a positive correlation with mTOR and seizure frequency. To identify the main expressing NogoA cell type, double staining revealed dysmorphic neuronal white matter cells. Increased NogoA expression is associated with profound inhibition of neuritic sprouting and therefore contributes to a decrease in neuronal network complexity in CCM patients.

Altered White Matter and Layer VIb Neurons in Heterozygous Disc1 Mutant, a Mouse Model of Schizophrenia.

Increased white matter neuron density has been associated with neuropsychiatric disorders including schizophrenia. However, the pathogenic features of these neurons are still largely unknown. Subplate neurons, the earliest generated neurons in the developing cortex have also been associated with schizophrenia and autism. The link between these neurons and mental disorders is also not well established. Since cortical layer VIb neurons are believed to be the remnant of subplate neurons in the adult rodent brain, in this study, we aimed to examine the cytoarchitecture of neurons in cortical layer VIb and the underlying white matter in heterozygous Disc1 mutant (Het) mice, a mouse model of schizophrenia. In the white matter, the number of NeuN-positive neurons was quite low in the external capsule; however, the density of these cells was found increased (54%) in Het mice compared with wildtype (WT) littermates. The density of PV-positive neurons was unchanged in the mutants. In the cortical layer VIb, the density of CTGF-positive neurons increased (21.5%) in Het mice, whereas the number of Cplx3-positive cells reduced (16.1%) in these mutants, compared with WT mice. Layer VIb neurons can be classified by their morphological characters. The morphology of Type I pyramidal neurons was comparable between genotypes while the dendritic length and complexity of Type II multipolar neurons were significantly reduced in Het mice. White matter neurons and layer VIb neurons receive synaptic inputs and modulate the process of sensory information and sleep/arousal pattern. Aberrances of these neurons in Disc1 mutants implies altered brain functions in these mice.

The enigmatic fetal subplate compartment forms an early tangential cortical nexus and provides the framework for construction of cortical connectivity.

The most prominent transient compartment of the primate fetal cortex is the deep, cell-sparse, synapse-containing subplate compartment (SPC). The developmental role of the SPC and its extraordinary size in humans remain enigmatic. This paper evaluates evidence on the development and connectivity of the SPC and discusses its role in the pathogenesis of neurodevelopmental disorders. A synthesis of data shows that the subplate becomes a prominent compartment by its expansion from the deep cortical plate (CP), appearing well-delineated on MR scans and forming a tangential nexus across the hemisphere, consisting of an extracellular matrix, randomly distributed postmigratory neurons, multiple branches of thalamic and long corticocortical axons. The SPC generates early spontaneous non-synaptic and synaptic activity and mediates cortical response upon thalamic stimulation. The subplate nexus provides large-scale interareal connectivity possibly underlying fMR resting-state activity, before corticocortical pathways are established. In late fetal phase, when synapses appear within the CP, transient the SPC coexists with permanent circuitry. The histogenetic role of the SPC is to provide interactive milieu and capacity for guidance, sorting, "waiting" and target selection of thalamocortical and corticocortical pathways. The new evolutionary role of the SPC and its remnant white matter neurons is linked to the increasing number of associative pathways in the human neocortex. These roles attributed to the SPC are regulated using a spatiotemporal gene expression during critical periods, when pathogenic factors may disturb vulnerable circuitry of the SPC, causing neurodevelopmental cognitive circuitry disorders.

Distribution, number, and certain neurochemical identities of infracortical white matter neurons in the brains of three megachiropteran bat species.

A large population of infracortical white matter neurons, or white matter interstitial cells (WMICs), are found within the subcortical white matter of the mammalian telencephalon. We examined WMICs in three species of megachiropterans, Megaloglossus woermanni, Casinycteris argynnis, and Rousettus aegyptiacus, using immunohistochemical and stereological techniques. Immunostaining for neuronal nuclear marker (NeuN) revealed substantial numbers of WMICs in each species-M. woermanni 124,496 WMICs, C. argynnis 138,458 WMICs, and the larger brained R. aegyptiacus having an estimated WMIC population of 360,503. To examine the range of inhibitory neurochemical types we used antibodies against parvalbumin, calbindin, calretinin, and neural nitric oxide synthase (nNOS). The calbindin and nNOS immunostained neurons were the most commonly observed, while those immunoreactive for calretinin and parvalbumin were sparse. The proportion of WMICs exhibiting inhibitory neurochemical profiles was ~26%, similar to that observed in previously studied primates. While for the most part the WMIC population in the megachiropterans studied was similar to that observed in other mammals, the one feature that differed was the high proportion of WMICs immunoreactive to calbindin, whereas in primates (macaque monkey, lar gibbon and human) the highest proportion of inhibitory WMICs contain calretinin. Interestingly, there appears to be an allometric scaling of WMIC numbers with brain mass. Further quantitative comparative work across more mammalian species will reveal the developmental and evolutionary trends associated with this infrequently studied neuronal population.

Increased densities of white matter neurons as a cross-disease feature of neuropsychiatric disorders.

While neurons of the human cerebral cortex are mainly distributed in the gray matter, the white matter (WM) also contains some excitatory and inhibitory neurons, so-called WM neurons. Studies on the cytoarchitectural alterations in the brains of patients with neuropsychiatric disorders have repeatedly reported increased densities of the WM neurons in a proportion of patients with schizophrenia and autism spectrum disorder. Although some studies have demonstrated increased densities of superficial WM neurons, others have demonstrated increased densities of deep WM neurons and increased WM neuron densities can be considered as one of the cross-disease features of neuropsychiatric disorders. Nevertheless, what actually causes the increase in the densities of the WM neurons still remains under debate, and several hypothetical mechanisms have been proposed. The WM neurons in normal brains are considered as remnants of the subplate neurons, which represent a transient cytoarchitectural zone present during development of the mammalian neocortex; it has been suggested that increased densities of the WM neurons could result from inappropriate apoptosis of the subplate neurons in the brains of patients with neuropsychiatric disorders. On the other hand, recent experimental studies have demonstrated that genetic and environmental factors that enhance the risk of development of neuropsychiatric disorders could cause altered distribution of neurons in the WM. To understand the pathophysiology underlying the increased densities of the WM neurons, it is important to investigate the cellular characteristics of the WM neurons in the brains of both normal subjects and patients with neuropsychiatric disorders.

Reduced cortical somatostatin gene expression in a rat model of maternal immune activation

Alterations in GABAergic interneurons and glutamic acid decarboxylase (GAD) are observed in the brains of people with schizophrenia. Studies also show increased density of interstitial white matter neurons (IWMN), including those containing GAD and somatostatin (SST) in the brain in schizophrenia. Maternal immune activation can be modelled in rodents to investigate the relationship between prenatal exposure to infections and increased risk of developing schizophrenia. We reported that maternal immune activation induced an increase in density of somatostatin-positive IWMN in the adult rat offspring. Here we hypothesised that maternal immune activation induced in pregnant rats by polyinosinic:polycytidylic acid would alter SST and GAD gene expression as well as increase the density of GAD-positive IWMNs in the adult offspring. SST gene expression was significantly reduced in the cingulate cortex of adult offspring exposed to late gestation maternal immune activation. There was no change in cortical GAD gene expression nor GAD-positive IWMN density in adults rats exposed to maternal immune activation at either early or late gestation. This suggests that our model of maternal immune activation induced by prenatal exposure of rats to polyinosinic:polycytidylic acid during late gestation is able to recapitulate changes in SST but not other GABAergic neuropathologies observed in schizophrenia.

Projections to the putamen from neurons located in the white matter and the claustrum in the macaque.

Continuing investigations of corticostriatal connections in rodents emphasize an intricate architecture where striatal projections originate from different combinations of cortical layers, include an inhibitory component, and form terminal arborizations which are cell-type dependent, extensive, or compact. Here, we report that in macaque monkeys, deep and superficial cortical white matter neurons (WMNs), peri-claustral WMNs, and the claustrum proper project to the putamen. WMNs retrogradely labeled by injections in the putamen (four injections in three macaques) were widely distributed, up to 10 mm antero-posterior from the injection site, mainly dorsal to the putamen in the external capsule, and below the premotor cortex. Striatally projecting labeled WMNs (WMNsST) were heterogeneous in size and shape, including a small GABAergic component. We compared the number of WMNsST with labeled claustral and cortical neurons and also estimated their proportion in relation to total WMNs. Since some WMNsST were located adjoining the claustrum, we wanted to compare results for density and distribution of striatally projecting claustral neurons (ClaST). ClaST neurons were morphologically heterogeneous and mainly located in the dorsal and anterior claustrum, in regions known to project to frontal, motor, and cingulate cortical areas. The ratio of ClaST to WMNsST was about 4:1 averaged across the four injections. These results provide new specifics on the connectional networks of WMNs in nonhuman primates, and delineate additional loops in the corticostriatal architecture, consisting of interconnections across cortex, claustralstriatal and striatally projecting WMNs.

MAG induces apoptosis in cerebellar granule neurons through p75NTR demarcating granule layer/white matter boundary

MAG (Myelin-associated glycoprotein) is a type I transmembrane glycoprotein expressed by Schwann cells and oligodendrocytes, that has been implicated in the control of axonal growth in many neuronal populations including cerebellar granule neurons (CGNs). However, it is unclear whether MAG has other functions in central nervous system, in particular, in cerebellar development and patterning. We find that MAG expression in the cerebellum is compartmentalised resulting in increased MAG protein levels in the cerebellar white matter. MAG induces apoptosis in developing CGNs through p75NTR signalling. Deletion of p75NTR in vivo reduced the number of apoptotic neurons in cerebellar white matter during development leading to reduction in the size of white matter in the adulthood. Furthermore, we show that MAG impairs CGNs neurite outgrowth as consequence of MAG-induced apoptosis in CGNs. Mechanistically, we find that MAG/NgR1-induced cell death is dependent of p75NTR-mediated activation of JNK/cell death signalling pathway. Together, these findings identify the mechanisms by which MAG induces CGNs apoptotic activity, a crucial event that facilitates cerebellar layer refinement during development.