[Frontiers in Bioscience 2, d88-125, March 1, 1997]
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CROSS-TALK SIGNALS IN THE CNS: ROLE OF NEUROTROPHIC AND HORMONAL FACTORS, ADHESION MOLECULES AND INTERCELLULAR SIGNALING AGENTS IN LUTEINIZING HORMONE-RELEASING HORMONE (LHRH)-ASTROGLIAL INTERACTIVE NETWORK

Bianca Marchetti

Department of Pharmacology, Medical School, University of Catania, 95125 Catania, Laboratory of Biotech. Neuropharmacology, OASI Institute for Research and Care (IRCCS) on Mental Retardation and Brain Aging (IRCCS) Troina, (EN), Italy.

Received 8/2/96; Accepted 2/20/97; On-line 3/1/97

2. INTRODUCTION

Neurons have long been thought to represent the sole "information-processing" elements of the central nervous system (CNS). However, the anatomical proximity of the non-neuronal elements, called neuroglia, to the neuronal cells, makes these elements particularly suited for taking active roles in the functions of neural information processing. Knowledge on neuroglia has rapidly accumulated in the last decades, and an extraordinary body of evidence has now been assembled by different investigators from all fields of neuroscience, supporting a key role for the glia in neuronal physiopathology. Indeed, at nearly a century and a half from the time of development of knowledge about neuron-glia interactions (1-5), the possibility of signals passing from neurons to glial cells, and thus to other neurons opens-up many scenarios for intercellular/intracellular crosstalk within single cells of the CNS (Fig. 1).

Figure. 1. The neuronal-astroglial network. Schematic representation of the networks of signals leaving the neuronal cells, signaling the astroglial cell, and finally returning back information to other neuronal cells.

The concept of the existence, in the CNS, of dynamic neuronal-glial signaling processes long thought to be only by virtue of passive transmission of information between these two major cell types (6-9), is now firmly established (10-17). Indeed, in the first description of glia, they were thought to form a connective or ground substance ("Binddesubstanz"), a sort of cement or neural glue (Neuroglia) in which the nerve elements are immersed (1,2). Not consistent with this early idea, the stellate cell "sternformigen Zellen", the star-shaped cell of Golgi, (18), designated as "astrocytes" by Lenhossek (19) and described by Raff and colleagues (20) as the type 2 astrocyte (see Fig. 2), has a neuronal "makeup" in culture.

Figure. 2. Immunohistochemical localization of glial fibrillary acidic protein (GFAP) in pure astroglial cultures and neuron-glial mixed cultures. Primary rat astrocytes were prepared and isolated from cerebral hemispheres and cultured as described (41) during in vitro maturation and differentiation. Immortalized hypothalamic luteinizing hormone-releasing hormone (LHRH) neurons were cultured on the top of 12 day-old astroglial cultures. Cytoplasmatic staining performed on fixed cells with monoclonal antibody to glial-fibrillary protein. A. GFAP staining in astrocyte cultures. B. GFAP staining during neuron-glia interactions.

This resemblance to neurons is further supported by its surface antigens (20) and ion channels (13, 14, 16, 17, 21-23), and in recent decades, this and other evidence, has led to alteration of the idea of a solely supportive role of the astrocytes to the concept of a more central and significant position of astrocytes in the metabolism and functioning of the CNS. Indeed, the anatomical proximity of astrocytes to neuronal synapses and the blood brain barrier (Fig. 3) makes these cells ideally suited for taking an active role in the ion, water and neurotransmitter metabolism of the CNS during both normal and abnormal neuronal function (13, 24-30).

Figure 3. Relationship between astrocytes and other brain elements. The schematic drawing illustrates several possible contacts between the astrocyte and 1. a synaptic cleft; 2. other astrocyte networks; 3. capillary/blood vessel; 4. neuronal cell bodies; 5. Nodes of Ranvier (see 14).

While Kuffler and Nichols first (7) recognized that interactions between neurons and glial cells would necessarily involve diffusible substances within the brain extracellular space, the functional significance of this "transmission" has not been clearly elucidated. Nonetheless, glial cells have been suggested to play a key role in the regulation of neuronal excitability, the modulation of synaptic transmission and neuronal connectivity, as well as the processing of information associated with learning and memory (24, 27, 31). The role of astroglia and infiltrating, inflammatory cells (monocytes and neutrophils) as well as cytokines and growth factors in the dynamics of CNS injury and disease constitute an important chapter of neuron-glia interactions (see 32). In particular, potential biochemical interactions between reactive glial cells (the microglial compartment) and damaged neurons have been hypothesized together with a suspected contribution of the immune system to neuronal death (see 32-40).

In the present work, a brief review on some aspects of the dialogue between the neuronal and glial cells will be presented. The recently disclosed network of interactions between the hypothalamic luteinizing hormone-releasing hormone (LHRH) neuronal system and astroglial cells will be discussed. Different dynamic "in vitro" models together with a number of pharmacological tools are proposed to unravel the LHRH-glial relationship at the biochemical and cellular levels. A key regulatory function of astroglia in the differentiation and maturation of the LHRH neuron is suggested on the basis of such experimental paradigms (41-44).

2.1. Pathways involved in neuron-glia communications

The functioning of the nervous system depends upon a continuos and sophisticated interrelationship between neuronal and glial cells. There are two broad subgroups of glial cells: the macroglia which consists of astrocytes, oligodendrocytes and ependymal cells, and the microglia. In recent years, an array of neurotransmitters, receptors, ion channels, adhesion molecules, and trophic factors have been revealed to be associated with glial cells. An insight about some of the factors that contribute to the neuron-astroglial signaling is presented.

2.2. Orchestration of neuronal migration by cell Surface and extracellular matrix molecules

During development and in the adult brain, astroglia have many different functions . An important facet of neuron-glia interactions concerns the key role of glia in the process of neuronal migration during embryogenesis (see 45-48). Glial-derived neuronal migration is a well recognized phenomenon in different regions of the developing mammalian brain. The migration of neuronal precursors to their final locations and the projection of axons to their appropriate targets are two critical events in neural development that require cell-cell and cell-matrix interactions. Migration of neurons is a remarkable process that relies on chemical communication between many different cells. Axon guidance and target recognition are achieved by highly specific chemical mechanisms using diffusible trophic factors, cell surface and extracellular matrix molecules which allow tropism and cell-cell interactions (46, 48-50). In both the cerebral cortex and the cerebellum, cells have been shown to utilize glial processes as guides in migration (46, 47). Neurons use glial fibers, which radiate from the brain's inner to outer surfaces, as a highway to carry them through the brain and to their final destination. In the neural crest, precursor cells must use a series of cellular and extracellular matrix cues to reach their destinations (see 50, for review). Many factors including genetic mutations, radiation and drugs such as cocaine and alcohol, can interfere with the process of neuron migration, leading to brain abnormalities ranging from epilepsy, to mental retardation and hypogonadism.

Cell adhesion molecules (CAMs) and components of the extracellular matrix (ECM) mediate, at least in part, the neuron-glia interactions. Indeed, astroglia express a number of cell or substrate adhesive molecules along the pathways of developing axonal tracts. Certain populations of astrocytes may also express other extracellular matrix molecules during development, after injury, or during degenerative diseases, that are inhibitory for axonal outgrowth. The majority of cell adhesion molecules described in the CNS can be ascribed to two growing gene families, such as the cadherin superfamily for the calcium-dependent and the immunoglobulin superfamily for the calcium-independent adhesion mechanisms (50). Furthermore, ECM components like laminin , fibronectin or proteoglycans and integrin-type receptors are expressed in developing neural tissues. In certain regions of the CNS during development, pioneering neurites may growth along pre-formed pathways of neuroepithelial cells, which later develop into astroglia. These cells express laminin as well as neural cell adhesion molecule, N-CAM and N-cadherin, on their surface. It is believed that the combined expression of these growth promoting molecules may help to direct growing neurites to specific regions of the developing brain (see 50).