Neuroglia

Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. The neuroglia make up more than one half the volume of neural tissue in our body. [1] They maintain homeostasis, form myelin in the peripheral nervous system, and provide support and protection for neurons.[2] In the central nervous system, glial cells include oligodendrocytes, astrocytes, ependymal cells, and microglia, and in the peripheral nervous system they include Schwann cells and satellite cells.

neuroglia

In general, neuroglial cells are smaller than neurons. There are approximately 85 billion glia cells in the human brain,[8] about the same number as neurons.[8] Glial cells make up about half the total volume of the brain and spinal cord.[27] The glia to neuron-ratio varies from one part of the brain to another. The glia to neuron-ratio in the cerebral cortex is 3.72 (60.84 billion glia (72%); 16.34 billion neurons), while that of the cerebellum is only 0.23 (16.04 billion glia; 69.03 billion neurons). The ratio in the cerebral cortex gray matter is 1.48, with 3.76 for the gray and white matter combined.[27] The ratio of the basal ganglia, diencephalon and brainstem combined is 11.35.[27]

While glial cells in the PNS frequently assist in regeneration of lost neural functioning, loss of neurons in the CNS does not result in a similar reaction from neuroglia.[18] In the CNS, regrowth will only happen if the trauma was mild, and not severe.[40] When severe trauma presents itself, the survival of the remaining neurons becomes the optimal solution. However, some studies investigating the role of glial cells in Alzheimer's disease are beginning to contradict the usefulness of this feature, and even claim it can "exacerbate" the disease.[41] In addition to affecting the potential repair of neurons in Alzheimer's disease, scarring and inflammation from glial cells have been further implicated in the degeneration of neurons caused by amyotrophic lateral sclerosis.[42]

In recent years, increasing evidence regarding the functional importance of lipid droplets (LDs), cytoplasmic storage organelles in the central nervous system (CNS), has emerged. Although not abundantly present in the CNS under normal conditions in adulthood, LDs accumulate in the CNS during development and aging, as well as in some neurologic disorders. LDs are actively involved in cellular lipid turnover and stress response. By regulating the storage of excess fatty acids, cholesterol, and ceramides in addition to their subsequent release in response to cell needs and/or environmental stressors, LDs are involved in energy production, in the synthesis of membranes and signaling molecules, and in the protection of cells against lipotoxicity and free radicals. Accumulation of LDs in the CNS appears predominantly in neuroglia (astrocytes, microglia, oligodendrocytes, ependymal cells), which provide trophic, metabolic, and immune support to neuronal networks. Here we review the most recent findings on the characteristics and functions of LDs in neuroglia, focusing on astrocytes, the key homeostasis-providing cells in the CNS. We discuss the molecular mechanisms affecting LD turnover in neuroglia under stress and how this may protect neural cell function. We also highlight the role (and potential contribution) of neuroglial LDs in aging and in neurologic disorders.

Autism is a complex neurodevelopmental disorder of early onset that is highly variable in its clinical presentation. Although the causes of autism in most patients remain unknown, several lines of research support the view that both genetic and environmental factors influence the development of abnormal cortical circuitry that underlies autistic cognitive processes and behaviors. The role of the immune system in the development of autism is controversial. Several studies showing peripheral immune abnormalities support immune hypotheses, however until recently there have been no immune findings in the CNS. We recently demonstrated the presence of neuroglial and innate neuroimmune system activation in brain tissue and cerebrospinal fluid of patients with autism, findings that support the view that neuroimmune abnormalities occur in the brain of autistic patients and may contribute to the diversity of the autistic phenotypes. The role of neuroglial activation and neuroinflammation are still uncertain but could be critical in maintaining, if not also in initiating, some of the CNS abnormalities present in autism. A better understanding of the role of neuroinflammation in the pathogenesis of autism may have important clinical and therapeutic implications.

The name neuroglia is generally translated as nerve glue. In the recent past, this has been used to describe passive structural cells. Presently, this view has been challenged and the true dynamic and multifunctional nature of neuroglia is beginning to be appreciated. In the central nervous system, the main kinds of neuroglia are astrocytes (the primary homeostatic cells that ensure synaptic transmission), oligodendrocytes (which form the myelin that ensures rapid electrical transmission) and microglia (the main immune cells). In the peripheral nervous system, neuroglia comprise Schwann cells, satellite glia and enteric glia. These functionally diverse and specialised cells are fundamental to function at the molecular, cellular, tissue and system levels. Without nerve glue, the body cannot function and the future will begin to unlock their importance in higher cognitive functions that set humans apart from other animals and their true potential as therapeutic targets in neurodegenerative and other diseases.

Neurons, neuroglia (astrocytes and oligodendrocytes), and ependymal cells are three distinct categories of neural cells in the central nervous system. In the mature brain and spinal cord, the classical histological criteria define these cells by their microscopic structure very well. During development, the precursors for all of these cells reside within the epithelium of the neural plate and its successor, the neural tube. These precursor cells are the undifferentiated, primitive neuroepithelium of the classical literature. As the cerebral vesicles enlarge and their walls thicken, the primitive neuroepithelial cells elongate, maintaining a radial orientation until they migrate. Although many, but not all, of these cells span the extent of the ventricular wall, they are the precursors of neurons, neuroglia, and ependymal cells. Thus, it is useful to retain their classical designation as primitive neuroepithelial cells and to treat them as neural precursor cells. Neural precursor cells are neither neuroglia nor neurons. It is not appropriate to call them radial glial cells anymore than it is to call them radial neuronal cells. The term "radial glia" has long been used to describe the mature, elongated astrocytes, represented by Bergmann cells in the cerebellum and Müller cells in the retina. Inevitably, during development, transitional forms between neural precursor cells and the neurons, neuroglia, and ependymal cells will occur. Such transitional cells are known as neuroblasts, glioblasts, or ependymoblasts, even though they may be postmitotic. Alternative terms are "immature neurons," "immature neuroglia," and "immature ependymal cells." The migration of many neural precursor cells is accomplished by translocation rather than free cellular locomotion. There is both direct and indirect evidence to document the translocation of the nuclear/perikaryal/somal complex through the leading process of primitive neuroepithelial cells. This is conspicuous in the neocortex, where the discrete radial arrangement of pyramidal cells may result from translocation of neuroblasts, while their leading processes still contact the pial surface. Migration by translocation occurs throughout the CNS. GLIA 43:6-18, 2003.

While thyroid hormone impacts glial function in various manner (see above), neuroglia is not only target but also the predominant source of T3 in the brain. As mentioned above, astrocytes and tanycytes express type 2 deiodinase (D2), the enzyme catalyzing thyroid hormone activation. Below, we will discuss factors and conditions affecting D2 regulation in glial cells, since they can contribute to the better understanding of thyroid hormone signaling in the brain.

Astrocytes and tanycytes of the neuroglial compartment are the predominant source of T3 present in the brain while TR in neurons represents a major target of thyroid hormone. As discussed above, neurons cannot generate T3 but express type 3 deiodinase (D3), the T3 degrading enzyme. While numerous observations suggested that glial thyroid hormone metabolism could affect neuronal function (see Section 3.1), until recently no direct evidence could be obtained to prove the existence of deiodinase-mediated transcriptional T3 footprints in neurons. Recently a two-dimensional coculture was used based on the D2-expressing H4 glioma cells and the D3-expressing SK-N-AS neuronal cell line. It has been shown that T4 could activate the endogenously expressed T3-sensitive ENPP2 gene of the neuronal compartment only if the glial compartment was present. This model led to the demonstration that D2-mediated glial T3 generation from physiological amount of T4 can directly affect thyroid hormone-dependent gene expression in a paracrine fashion [23]. A different approach using expression profiling-based assessment of thyroid-hormone-regulated gene expression in the cerebral cortex of the MCT8, D2, and MCT8/D2 knock-out mice suggested that negative regulation required D2-generated T3, while peripheral T3 entering the brain should be sufficient to maintain normal expression of positively regulated genes [59].

Specific signals as hedgehog proteins [176, 182], bacterial lipopolysaccharide (LPS) [132, 133, 137, 183], and hypoxia [184] have been established as regulators of deiodinase activities. It was also studied how these specific signals impact neuroglial thyroid hormone metabolism in the coculture system. The sonic hedgehog morphogene decreases glial thyroid hormone activation via WSB1-mediated posttranslational downregulation of D2 (see Section 3.2) and increases neuronal D3 expression [23]. This demonstrates the existence of a mechanism ensuring a fine-tuned balance between sonic hedgehog-mediated proliferation and T3-evoked differentiation. This is interesting since astrocytes are targets of sonic hedgehog signaling [185]. It has been also demonstrated that in the brain T3 upregulates crucial elements of the sonic hedgehog signaling pathway that could represent a compensatory feedback loop for sonic hedgehog-mediated T3 regulation [186]. 041b061a72