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Neonatal hypothalamic c-fos expression in an excitotoxicity-induced model of precocious puberty
C E Smyth1, M Natarajan, M Wilkinson
1Department of Physiology and Biophysics, Dalhousie University, Halifax, NS, Canada.
Insights
Monosodium glutamate (MSG) induces precocious puberty in rats by targeting the hypothalamus, causing edema and FOS-like immunoreactivity (FLI). This effect is mediated by an MK-801-sensitive mechanism, but the exact receptor remains unidentified.
Area of Science:
- Neuroscience
- Endocrinology
- Toxicology
Background:
- Monosodium glutamate (MSG) is known to affect neuronal pathways.
- Precocious puberty can be induced by hypothalamic lesions in neonatal rats.
- FOS-like immunoreactivity (FLI) is a marker for neuronal activation.
Purpose of the Study:
- To identify the site of action of MSG in inducing precocious puberty in neonatal rats.
- To investigate the role of NMDA receptors in MSG-induced effects.
- To characterize the neurobiological mechanisms underlying MSG's impact on sexual maturation.
Main Methods:
- Immunocytochemical detection of c-fos expression (FLI) in neonatal rat brains.
- Administration of MSG and NMDA (N-methyl-D-aspartate) to induce precocious puberty.
- Treatment with NMDA receptor antagonist MK-801 and non-NMDA antagonist DNQX to block MSG effects.
Main Results:
- Single MSG doses induced precocious puberty, hypothalamic edema, and FLI in the arcuate nucleus (ARC) and circumventricular organs (CVO).
- NMDA, at a dose causing ARC FLI without edema, did not affect puberty.
- MK-801 pretreatment blocked MSG-induced edema and precocious puberty but altered FLI patterns, indicating a remaining NMDA-sensitive component.
Conclusions:
- MSG induces precocious sexual maturation through an MK-801-sensitive mechanism linked to basal hypothalamic edema.
- The precise receptor mediating MSG-induced c-fos expression in the presence of antagonists requires further investigation.
- The role of edema in MSG's excitotoxic action on inhibitory neurons warrants further study.
Abstract:
We have used immunocytochemical detection of c-fos expression (FOS-like immunoreactivity, FLI) to establish the site of action of monosodium glutamate (MSG) in neonatal rats in a model of lesion-induced precocious puberty. The primary target appears to be the hypothalamic arcuate nucleus (ARC) but other circumventricular organs (CVO) are also affected (e.g. subfornical organ). Single injections of MSG (1-4 mg/g single dose, postnatal day 2 (P2)) which result in precocious puberty induce an area of edema, surrounded by a ring of FLI in the basal hypothalamus. In contrast, a maximal sub-lethal dose of NMDA (N-methyl-D-aspartate; 3 mg/kg) which produces a different pattern of ARC FLI, without edema, has no effect on puberty. Multiple doses of MSG (4 mg/g P2, P4, P6, P8), consistent with severe ARC damage and resultant sterility, markedly attenuates the FLI response by P8, with no visible edematous reaction following the final injection. In efforts to block the effect of MSG, pretreatment with the NMDA receptor-specific antagonist MK-801 (dizocilpine maleate) prevented the appearance of edema, as well as the onset of precocious puberty. However, MK-801 did not completely eliminate the FLI, but transformed the pattern of staining so that the original edematous area now contained many FOS-positive cells. This remaining MSG-induced FLI could not be eliminated by higher doses of MK-801 or by the non-NMDA antagonist DNQX (6,7-dinitroquinoxaline-2,3-dione). The combination of MK-801 and DNQX was also ineffective. MK-801 or DNQX had no effect on FLI when injected alone (i.e., without MSG) or in combination. The receptor which mediates MSG-induced c-fos expression, in the presence of MK-801 or DNQX, needs to be identified. We conclude, in conjunction with our previous work, that MSG induces precocious sexual maturation via an MK-801-sensitive mechanism associated with an edematous response of the basal hypothalamus. Whether the appearance of edema is indicative of an excitotoxic action of MSG, resulting in the removal of neurons inhibitory to sexual maturation, remains to be established.