Neuronal dysfunction in the epileptic brain originating from glial cells

Neurogenesis involves generation of new neurons through finely tuned multistep processes, such as neural stem cell (NSC) proliferation, migration, differentiation, and integration into existing neuronal circuitry in the dentate gyrus of the hippocampus and subventricular zone. Adult hippocampal neurogenesis is involved in cognitive functions and altered in various neurodegenerative disorders, including Alzheimer disease (AD). Ethosuximide (ETH), an anticonvulsant drug is used for the treatment of epileptic seizures. However, the effects of ETH on adult hippocampal neurogenesis and the underlying cellular and molecular mechanism(s) are yet unexplored. Herein, we studied the effects of ETH on rat multipotent NSC proliferation and neuronal differentiation and adult hippocampal neurogenesis in an amyloid β (Aβ) toxin-induced rat model of AD-like phenotypes. ETH potently induced NSC proliferation and neuronal differentiation in the hippocampus-derived NSC in vitro. ETH enhanced NSC proliferation and neuronal differentiation and reduced Aβ toxin-mediated toxicity and neurodegeneration, leading to behavioral recovery in the rat AD model. ETH inhibited Aβ-mediated suppression of neurogenic and Akt/Wnt/β-catenin pathway gene expression in the hippocampus. ETH activated the PI3K·Akt and Wnt·β-catenin transduction pathways that are known to be involved in the regulation of neurogenesis. Inhibition of the PI3K·Akt and Wnt·β-catenin pathways effectively blocked the mitogenic and neurogenic effects of ETH. In silico molecular target prediction docking studies suggest that ETH interacts with Akt, Dkk-1, and GSK-3β. Our findings suggest that ETH stimulates NSC proliferation and differentiation in vitro and adult hippocampal neurogenesis via the PI3K·Akt and Wnt·β-catenin signaling.

This review synthesizes the emerging understanding of the roles of glial cells and non-coding RNAs (ncRNAs) in the pathogenesis and progression of Alzheimer’s disease and related dementias (ADRDs). ADRDs encompass a spectrum of neurodegenerative disorders characterized by cognitive decline, memory impairment, and functional deterioration. The interplay between the most common types of glial cells—astrocytes, microglia, and oligodendrocytes—and ncRNAs is emerging as a critical factor in the development of ADRDs. Glial cells are essential for maintaining homeostasis within the central nervous system (CNS); however, their dysregulation can lead to neuroinflammation and neuronal dysfunction, exacerbating neurodegeneration. Reactive astrocytes and activated microglia can create neurotoxic environments that further impair neuronal health. Concurrently, ncRNAs, particularly long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), have emerged as significant regulators of glial gene expression, influencing inflammatory responses and glial cell function. Understanding the complex interactions between glial cells and ncRNAs is crucial for developing targeted therapeutic strategies. By elucidating the mechanisms underlying their interactions, this review aims to highlight the critical importance of glial cells and ncRNAs in the context of neurodegenerative diseases, paving the way for innovative approaches to prevent and treat ADRDs. Ultimately, enhancing our understanding of these processes may lead to novel therapies and improved outcomes for individuals affected by these debilitating conditions.

Research over the past four decades has highlighted the importance of certain brain cells, called glial cells, and has moved the neurocentric vision of structure, function, and pathology of the nervous system toward a more holistic perspective. In this view, the demand for technologies that are able to target and both selectively monitor and control glial cells is emerging as a challenge across neuroscience, engineering, chemistry, and material science. Frequently neglected or marginally considered as a barrier to be overcome between neural implants and neuronal targets, glial cells, and in particular astrocytes, are increasingly considered as active players in determining the outcomes of device implantation. This review provides a concise overview not only of the previously established but also of the emerging physiological and pathological roles of astrocytes. It also critically discusses the most recent advances in biomaterial interfaces and devices that interact with glial cells and thus have enabled scientists to reach unprecedented insights into the role of astroglial cells in brain function and dysfunction. This work proposes glial interfaces and glial engineering as multidisciplinary fields that have the potential to enable significant advancement of knowledge surrounding cognitive function and acute and chronic neuropathologies.

<p indent=0mm>The cerebellum is the largest subcortical motor structure, mainly responsible for motor coordination and control. Cerebellar damage and dysfunction caused by hereditary or endogenous/exogenous factors will lead to cerebellar ataxia. Patients with cerebellar ataxia suffer from balance and gait dysfunction, limb movement deficits, oculomotor abnormalities, as well as dysarthria, which seriously affect their quality of life and constitute a heavy social and economic burden. However, the diverse pathogenesis poses great challenges in the prevention and treatment of cerebellar ataxia. Here we review the current knowledge of the etiology, symptoms, and clinical classification of cerebellar ataxia. The latest research progress on the neural mechanism of cerebellar ataxia has been summarized, in particular, from the view of the structure and dysfunction of neurons, neural circuits, and glial cells in the cerebellum. Furthermore, based on the current clinical treatment of cerebellar ataxia, we also propose and discuss the advantages and disadvantages of new strategies of targeting the neurotransmitter system of cerebellar circuitries, microglia-mediated neuroinflammation, virulence genes of hereditary cerebellar ataxia, as well as brain stimulation intervention during the treatment of cerebellar ataxia. This review may provide a useful reference for the development of more effective therapies for cerebellar ataxia in the future.

Neurodegenerative diseases are characterized by the dysfunction of neurons. Neural progenitor cells (NPCs) possess the ability to self-renew as well as differentiate into neuronal and glial cells. For these reasons, NPC neurogenesis has the potential to cure neurodegenerative diseases and restore human cognitive function. In the adult mammalian brain, NPCs are maintained in a specialized microenvironment called the neurovascular niche (NVN) where they reside close to brain microvascular networks (MVNs). To investigate the relationship between microvessels and NPCs, models of the human NVN have been developed in vitro. However, most of these systems do not replicate the complex cellular interactions and physical stimuli, such as interstitial and intravascular flow, found in the brain. In this work, we first used a microfluidic device (MFD) to develop brain MVNs comprised of human brain endothelial cells (BECs), pericytes, and astrocytes with (flow condition) and without (static condition) interstitial flow. We found that interstitial flow was beneficial for MVN formation through natural BEC morphogenesis (angiogenesis and vasculogenesis). Microvessels in flow conditions achieved anastomosis and perfusion, whereas those in static conditions lacked connectivity and were not perfused. Compared to static culture, microvessels in flow culture exhibited enhanced vascular morphology, astrocyte coverage, and basement membrane protein expression, as well as decreased dextran permeability. Moving forward, we introduced human NPCs to our MFD to simulate the NVN microenvironment. Compared to NPCs cultured alone, self-renewing NPCs co-cultured with brain MVNs experienced increased viability and expansion. Co-culture with brain MVNs also enhanced NPC neurogenesis, as demonstrated by increased number of mature neurons, total neurite extension, and spontaneous neuronal activity. Similarly, NPC neurogenesis was improved when co-cultured with brain MVNs under flow conditions, compared to static conditions. Collectively, these results highlighted the importance of interstitial flow in the generation of perfused brain MVNs in vitro and demonstrated the potential of our MFD to elucidate the biological and physical interactions that govern NPC self-renewal and differentiation. Knowledge generated from our model will be beneficial for the development of effective drug and NPC-based therapies for the treatment of neurodegenerative diseases.--Author's abstract

In the central nervous system (CNS), glial cells, such as microglia and astrocytes, are normally associated with support roles including contributions to energy metabolism, synaptic plasticity, and ion homeostasis. In addition to providing support for neurons, microglia and astrocytes function as the resident immune cells in the brain. The glial function is impacted by multiple aspects including aging and local CNS changes caused by neurodegeneration. During aging, microglia and astrocytes display alterations in their homeostatic functions. For example, aged microglia and astrocytes exhibit impairments in the lysosome and mitochondrial function as well as in their regulation of synaptic plasticity. Recent evidence suggests that glia can also alter the pathology associated with many neurodegenerative disorders including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Shifts in the microbiome can impact glial function as well. Disruptions in the microbiome can lead to aberrant microglial and astrocytic reactivity, which can contribute to an exacerbation of disease and neuronal dysfunction. In this review, we will discuss the normal physiological functions of microglia and astrocytes, summarize novel findings highlighting the role of glia in aging and neurodegenerative diseases, and examine the contribution of microglia and astrocytes to disease progression.

Neuroinflammation is involved in the onset or progression of various neurodegenerative diseases. Initiation of neuroinflammation is triggered by endogenous substances (damage-associated molecular patterns) and/or exogenous pathogens. Activation of glial cells (microglia and astrocytes) is widely recognized as a hallmark of neuroinflammation and triggers the release of proinflammatory cytokines, leading to neurotoxicity and neuronal dysfunction. Another feature associated with neuroinflammatory diseases is impairment of the blood-brain barrier (BBB). The BBB, which is composed of brain endothelial cells connected by tight junctions, maintains brain homeostasis and protects neurons. Impairment of this barrier allows trafficking of immune cells or plasma proteins into the brain parenchyma and subsequent inflammatory processes in the brain. Besides neurons, activated glial cells also affect BBB integrity. Therefore, BBB dysfunction can amplify neuroinflammation and act as a key process in the development of neuroinflammation. BBB integrity is determined by the integration of multiple signaling pathways within brain endothelial cells through intercellular communication between brain endothelial cells and brain perivascular cells (pericytes, astrocytes, microglia, and oligodendrocytes). For prevention of BBB disruption, both cellular components, such as signaling molecules in brain endothelial cells, and non-cellular components, such as inflammatory mediators released by perivascular cells, should be considered. Thus, understanding of intracellular signaling pathways that disrupt the BBB can provide novel treatments for neurological diseases associated with neuroinflammation. In this review, we discuss current knowledge regarding the underlying mechanisms involved in BBB impairment by inflammatory mediators released by perivascular cells.

Pluripotent stem cell-based models of spinal muscular atrophy.

The effects of copper sulfate on the structure and function of the rat cerebellum: A stereological and behavioral study

Chapter 15 - Metals and Mitochondria in Neurodegeneration

We performed volume-selective proton magnetic resonance spectroscopy (1H-MRS) of the brain with a 1.5 T magnet in 28 patients with autism, and compared the results with those from 28 age-matched patients with unclassified mental retardation and 25 age-matched healthy children. Peaks for N-acetylaspartate, choline and creatine, but not lactate, were observed in each group on 1H-MRS. The N-acetylaspartate/choline ratio was lower in patients with mental retardation than in patients with autism and controls (P = .05, respectively). However, there were no differences in the N-acetylaspartate/ choline ratios between patients with autism and controls, and the N-acetylaspartate/creatine and choline/creatine ratios did not differ among the three groups. These results suggest that N-acetylaspartate is decreased in patients with mental retardation and that a disorder or dysfunction of neurons in the brain exists. There also appear to be differences in the brain lesions or dysfunctions found in patients with autism and mental retardation.

Mutations are at the root of many human diseases. Still, we largely do not exactly understand how they trigger pathogenesis. One, more recent, hypothesis has been that they comprehensively perturb protein-protein interaction (PPI) networks and significantly alter key biological processes. Under this premise, many rare genetic disorders with Mendelian inheritance, like Huntington's disease and several spinocerebellar ataxias, are likely to be caused by complex genotype-phenotype relationships involving abnormal PPIs. These altered PPI networks and their effects on cellular pathways are poorly understood at the molecular level. In this review, we focus on PPIs that are perturbed by the expanded pathogenic polyglutamine tract in huntingtin (HTT), the protein which, in its mutated form, leads to the autosomal dominant, neurodegenerative Huntington's disease. One aspect of perturbed mutant HTT interactions is the formation of abnormal protein species such as fibrils or large neuronal inclusions as a result of homotypic and heterotypic aberrant molecular interactions. This review focuses on abnormal PPIs that are associated with the assembly of mutant HTT aggregates in cells and their potential relevance in disease. Furthermore, the mechanisms and pathobiological processes that may contribute to phenotype development, neuronal dysfunction and toxicity in Huntington's disease brains are also discussed. This article is part of the Special Issue "Proteomics".

Epilepsy, affecting about 1% of the population, comprises a group of disorders of brains characterized by periodic and unpredictable occurrence of seizures. Seizures are medically intractable in about 30% of patients suffering from epilepsy, they have no response to anti-epileptic drugs (AED) which are currently being used in clinical field. Decades of efforts of scientists has demonstrated glial cells' very crucial role in neuron network. They not only serve to maintain homeostasis, but also interfere communication and general regulation. As the consequence, glial cells also go through damage and lesion during seizures and epilepsy, which further exacerbate pathological condition. This hypothesis can account for lots of AED refractory cases because most of AEDs target only neurons' lesion. In a number of experiments, scientists have demonstrated this hypothesis by finding various striking lesion in glial cells before; during; after epilepsy. Blocking water channels and potassium channels over-expressed by astrocytes; blocking gap junction to decrease diffusion in glial networks; locating these lesion of glial cells and then neutralize the dysfunction are very promising ideas of designing drugs alleviating epilepsy. This paper introduces basic characters of glial cells, putting emphasis on their abnormalities within epileptic brains, corresponding therapy will be discussed.

In brain, gap junctions are widely expressed in various cell types including neurons and glial cells. They are present between neurons at electrical synapses (Bennett, 1977) and provide the intercellular pathway for astrocytic networks (Giaume and McCarthy, 1996). We have recently reviewed the expression of gap junctions in the central nervous system and discussed their physiopathological relevance in several brain dysfunctions (Rouach et al., 2002b). In the present chapter, we focus on the expression and function of connexins (Cxs) in a major glial cell population, the astrocytes, that outnumber neurons and make up about 50% of human brain volume (Tower and Young, 1973). Data indicating that astrocytic connexins represent an identified target of neuroglial and glial-glial interactions and that changes in their properties and/or their pattern of expression may be relevant in physiopathological situations are described. With that objective, we concentrate on the role of glutamate, which plays a key role in neurotoxic processes, and as a working hypothesis we discuss the potential contribution of astrocyte gap junctional communication (GJC) in the homeostasis of this excitatory amino acid.

Intracerebral hemorrhage (ICH) is a highly harmful neurological disorder with high rates of mortality, disability, and recurrence. However, effective therapies are not currently available. Secondary immune injury and cell death are the leading causes of brain injury and a poor prognosis. Pyroptosis is a recently discovered form of programmed cell death that differs from apoptosis and necrosis and is mediated by gasdermin proteins. Pyroptosis is caused by multiple pathways that eventually form pores in the cell membrane, facilitating the release of inflammatory substances and causing the cell to rupture and die. Pyroptosis occurs in neurons, glial cells, and endothelial cells after ICH. Furthermore, pyroptosis causes cell death and releases inflammatory factors such as interleukin (IL)-1β and IL-18, leading to a secondary immune-inflammatory response and further brain damage. The NOD-like receptor protein 3 (NLRP3)/caspase-1/gasdermin D (GSDMD) pathway plays the most critical role in pyroptosis after ICH. Pyroptosis can be inhibited by directly targeting NLRP3 or its upstream molecules, or directly interfering with caspase-1 expression and GSDMD formation, thus significantly improving the prognosis of ICH. The present review discusses key pathological pathways and regulatory mechanisms of pyroptosis after ICH and suggests possible intervention strategies to mitigate pyroptosis and brain dysfunction after ICH.