[Frontiers in Bioscience 2, d88-125, March 1, 1997]

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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

9. LHRH Neuron-Astroglia Interactions in the Adult Brain

In the adult rodent, LHRH is synthesized by diffusely organized forebrain neurons which are scattered over a continuum extending from the septal region anteriorly to the premamillary area, with the heaviest concentration in the anterior hypothalamus, the preoptic area and the septum, with fibers projecting not only to the median eminence but also through the hypothalamus and midbrain (218). During this passage, LHRH neurons are known to interact with many types of neurons and glia. Indeed, the architecture of the arcuate nucleus of the hypothalamus is unique in the arrangement of the glial cells within it. The architecture of the arcuate nucleus of the hypothalamus is unique in the arrangement of the glial cells within it. Tanycytes, specialized ependymal cells, line the ventricular wall and send their processes in an arching trajectory toward the surface of the brain (219). Astrocytes of varying morphologies (3) are also located in this region (220, 221). The contribution of glial elements to LHRH axonal targeting was suggested by the early experiments of Kozlowski and Coates (222) demonstrating the existence of ependymal tunnels and their association with LHRH axons. More recently, relationships of glia to LHRH axonal outgrowth from third ventricular grafts in hypogonadal mice have been described by Silverman and coworkers (223). Due to the absence of a functional gene for the neuropeptide LHRH, the hypogonadal (hpg) mice have infantile reproductive tract in adulthood, a condition that can be reversed by the implantation of normal fetal preoptic area tissue that contains LHRH neurons. Interestingly, LHRH axons were found adjacent to glial elements along their entire course from the graft-host interface, and appeared to exit via glial channels (223). Glial processes seem to provide a permissive substrate for LHRH axonal extension and the presence of chemotropic factors specific for the region of the median eminence underlie the accurate navigation of the growing axon as been suggested by Silverman and collaborators (223). The fact that LHRH axons display a remarkable degree of outgrowth during a time of extensive glial hypertrophy and hyperplasia suggests that the glia may play a facilitatory or permissive role in this particular system (223).

Then, in view of the high requirement for signaling environmental conditions to the LHRH neuronal system, and due to the paucity of synaptic inputs to the LHRH neurons , it seems reasonable to hypothesize that LHRH-astroglial interactions may play a key role in the successful decodification and transduction of appropriate signals from the different regions involved in the control of LHRH release. In fact, besides the conventional regulation of LHRH secretion at the level of LHRH cell bodies or terminals at the median eminence (ME), it seems quite apparent that LHRH may locally be modulated by dynamic relationships among neuron terminals, glia and basal lamina (see next sections), as already demonstrated for oxytocin and vasopressin (224) (Fig. 9). Indeed, based on electron microscopic results, King and Letourneau (225) have recently described that LHRH terminals in the median eminence (ME) undergo dramatic changes after gonadal hormone withdrawal, and a possible direct action of "intervening non neuronal (glial) elements", of the ME, has been suggested (225). Kohama and coworkers (226) have recently demonstrated that glial fibrillary acidic protein (GFAP), the main component of the intermediate filaments in cells of astroglial lineage, increases during proestrus in astrocytes of the hypothalamic arcuate nucleus (ARC) (226). Moreover, these changes were associated with altered astrocyte-neuron contacts and synaptic remodeling, during preparation for the preovulatory gonadotropin surge (227). Interestingly, hypothalamic distribution of astrocytes is gender-related (227). The work of Finch and coworkers has also recently found evidence that GFAP in the thalamus and hypothalamus increases with reproductive aging (228), while food restriction delays the age-related increase in GFAP mRNA expression in the hypothalamus (229). Finally, the development of astrocytes immunoreactive for GFAP in the MBH of hypogonadal mice revealed a marked increase for the glial fibrillary protein (230).

Of major importance, the studies of Ojeda and collaborators (186-190) have indicated a key role of astroglia-derived factors in the stimulation of LHRH release and induction of precocious puberty by the lesions of the female rat hypothalamus. Brain injury is known to result in the appearance of various mitogenic and neurotrophic activities in the area surrounding the lesion (see 188). Evidence has been provided that lesions of the preoptic-anterior hypothalamic (POA-AHA) area which induce precocious puberty, result in enhanced expression of the epidermal growth factor receptor (EGF-R) gene in reactive astrocytes (189, 190) surrounding the lesion site. Transforming growth factor a (TGF-alpha) is thought to mediate the puberty advancing effect of POA-AHA lesions on sexual development via its stimulatory effect on LHRH secretion (187-190). These effects have been postulated to require the glial cells as an intermediary, which upon TGF-alpha stimulation produce prostaglandins that act on the LHRH nerve terminals to enhance LHRH release (see 187). Therefore, it has been suggested, that the simultaneous increase in EGFR and TGF-alpha in reactive astrocytes may provide the necessary amplification for TGF-alpha to exert its stimulatory effects on LHRH secretion and cause sexual precocity (for comprehensive review see 190).