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Decrease of (+)-3-[125I]MK-801 binding to NMDA brain receptors revealed at puberty in rats treated neonatally with
R E Otoya1, A M Seltzer, A O Donoso
1Laboratorio de Investigaciones Cerebrales, LINCE, CRICYT-CONICET, Mendoza, Argentina.
Insights
Neonatal monosodium glutamate (MSG) exposure causes hypothalamic lesions and alters N-methyl-D-aspartic acid (NMDA) receptor binding in rats, particularly during puberty. These changes in NMDA receptors may contribute to neuroendocrine and behavioral abnormalities.
Area of Science:
- Neuroendocrinology
- Neuropharmacology
- Developmental Neuroscience
Background:
- Neonatal monosodium glutamate (MSG) administration to rodents causes obesity, infertility, and neuroendocrine dysfunction due to hypothalamic lesions.
- N-methyl-D-aspartic acid (NMDA) receptors are implicated in the development of these lesions and may be affected by neuronal dysfunction, impacting glutamatergic pathways.
- Understanding the precise effects of MSG on NMDA receptors is crucial for elucidating the mechanisms behind MSG-induced neuroendocrine and behavioral alterations.
Purpose of the Study:
- To investigate the scope of MSG-induced lesions in the hypothalamus.
- To determine the impact of neonatal MSG administration on NMDA receptor expression and binding.
- To correlate changes in NMDA receptor binding with neuroendocrine and behavioral outcomes in rats.
Main Methods:
- Neonatal rats were treated with MSG (4 mg/g) or saline (controls).
- Brains were examined at 4, 8, and 40 days of age, focusing on coronal cuts at the arcuate-median eminence level.
- NMDA receptor binding was quantified using autoradiography with the ligand (+)-3-[125I]MK-801.
Main Results:
- NMDA receptor labeling was higher in younger rats (4 and 8 days) compared to 40-day-old rats in both control and MSG-treated groups.
- At puberty (40 days), MSG-treated rats showed significantly impaired augmentation of MK-801 binding in specific hypothalamic areas.
- A ~50% reduction in NMDA binding sites was observed in the hippocampus (CA3) and cerebral cortex (parietal cortex) of 40-day-old MSG-treated rats compared to controls.
Conclusions:
- While NMDA receptors in the hypothalamus may initially appear normal after MSG lesioning, their expression is altered by puberty.
- MSG-induced neuroendocrine and behavioral abnormalities are likely partly mediated by decreased NMDA receptor density in the hippocampus and cerebral cortex.
- These findings highlight the long-term impact of early-life excitotoxic insults on neurodevelopment and receptor function.
Abstract:
Obesity, altered pattern of gonadal hormone secretion, advanced vaginal opening, irregular cycling, altered sexual behavior and infertility are the effects of the neonatal administration of monosodium glutamate (MSG) to rodents. These are the consequences of lesions located mainly in the hypothalamic region. It is believed that the receptors to N-methyl-D-aspartic acid (NMDA) actively participate in the onset and development of such lesions, on the other hand, they may be altered by neuronal dysfunction as well, seriously compromising the glutamatergic pathways that are involved in the neuroendocrine regulation. To clarify the scope of the lesion induced by MSG and its probable effects on the NMDA receptors, we measured them with a very sensitive ligand for autoradiography, (+)-3-[125I]MK-801. Coronal cuts at the level of the arcuate-median eminence of brains from 4-, 8- and 40-day-old rats treated neonatally with MSG (4 mg/g) or saline (controls) were examined. In the normal hypothalamus, NMDA receptor labelling was higher in the young animals than in the 40-day-old animals, and this was observed in both control and treated rats. NMDA receptor labelling of rats at puberty was very low, and no apparent differences were observed between groups. In contrast, in areas where an increase in NMDA binding sites normally occurs with development, a significant impairment of the normal augmentation of MK-801 binding was revealed. In the hippocampal layers, stratum radiatum and stratum oriens and in the cerebral cortex of 40-day-old rats treated with MSG a lower amount of binding was observed, of about 50% fewer sites compared to the untreated controls at the level of CA3 and in the outer layer of the parietal cortex. These results suggest that at an early stage of the MSG lesion the NMDA receptors located in the hypothalamus and other brain areas are apparently expressed normally, but at puberty the effects of the lesion are revealed in the hippocampus and cerebral cortex by a decrease in the density of binding. Thus, the abnormal neuroendocrine and behavioral responses displayed by the MSG-treated rats may be contributed partially by the alteration of the NMDA receptors in these areas.
