Conclusions

The importance of glia has become increasingly clear with the development of molecular biology and cell culture techniques. With technical progress, the roles of glia in neuronal migration in the development of neuronal pathways as well as in synaptic functions have been deciphered. Increasingly, the molecules involved in developmental processes and in the adult are being identified; molecules necessary for the migration of neurons on radial glia or Bergmann cells are made by neurons or glia with multiple interactions. Molecular studies of developmental mutants and human pathologies have led to the identification of the involvement of glia in numerous defects of migration that lead to microcephaly and other developmental diseases.

In many cases, axonal guidance seems to involve preformed glial pathways that may remain and create glial boundaries. Increasingly these neuroglial interactions are being identified in relation to neuronal functions. Because of their mobility and plasticity, glial cells appear to be increasingly involved in the functions of the cabled neuronal network (Fig. 4). Synapses throughout the brain are ensheathed by astrocytes. Astrocytes help to maintain synaptic functions by buffering ion concentrations, clearing released neuro-transmitters, and providing metabolic substrates to synapses. As recently reviewed, glia should be envisaged as integral modulary elements of tripartite synapses because they are now playing an active role in synaptic transmission and are fully involved in neuron-astrocytes circuits in the processing of information in the brain. They are indispensable in obtaining nutrients from the blood and helping to maintain the blood-brain barrier. For energy metabolism, these glial cells take up glucose from the brain capillaries and transform it into lactate and other fuels absolutely necessary for the neurons to function. The metabolic coupling between glia and neurons is increasingly obvious in view of the development of the methods of investigation, even in vivo; astrocytes contribute to the deoxyglucose signal in PET, which may give new insights into the interpretation of this signal in neurological and psychiatric disorders. As-trocytes are necessary to avoid the excitotoxic role of glutamate through the glutamate-glutamine cycle, which is pivotal, as are probably other neurotransmit-ter cycles. One of the recent developments is the way in which communication can occur through glial cells by calcium waves; this seminal discovery has been followed by a wealth of work demonstrating that calcium signaling can extend even to neurons and can be bidirectional. It is possible that astrocytes may provide new means of communication in the nervous system and new pathways not yet clearly defined. No doubt, there are enormous gaps to fill in relation to their functions in vivo: hints have been provided, for example, by the observation that they are modulated by circadian rhythms and hormonal states.

Although myelin repair and synaptic remodeling and regeneration can occur, many enigmas still remain, especially in humans, in which the factors may be different from those in the murine species. Thus, studies in primates and in vivo systems cannot be omitted at this stage in view of therapeutic implications.

The dysfunction of glial cells is possibly at the origin of many of the degenerative diseases of the nervous system and the major brain tumors (glioma). Although the neuroimmunological role of astrocytes as antigen presenting cells is still unclear in the CNS under in vivo conditions, their role in neurodegenerative diseases seems increasingly evident because they are implicated in the suppression of oxidative stress. No doubt, in the near future, we will understand more about the cross talk between glial cells and neurons in normal and pathological states. Already, abnormal astrocytes and oligodendrocytes appear to be involved in cognitive functions as evidenced from leukodystrophies related to oligodendrocyte or astrocyte genetic disorders. Recently, the primary genetic defect of Alexander disease was demonstrated in astrocytes where mutations of GFAP lead to a secondary demyelinating disease, enlightening the pivotal role of astrocyte on oligodendrocyte and myelin maintenance.

Progress in neuroscience has shown that neurons and glia do not represent just the addition of independent compartments and that the cooperation of both cell populations is essential for development and functions of the nervous system. As mentioned by Peschanski, the time has come for "neurogliobiology" because neurons and glia (including astrocytes, oligo-dendrocytes, and microglia) in the nervous system are undissociable partners.

See Also the Following Articles

BRAIN LESIONS • CIRCADIAN RHYTHMS • GABA • GLIAL CELL TYPES • NERVOUS SYSTEM, ORGANIZATION OF • NEURON

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