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Neuroglial Responses to Elevated Glutamate in the Medial Basal Hypothalamus of the Infant Mouse^{1 ,2}

Reproductive Endocrinology Center, Department of Ob/Gyn and Reproductive Sciences, University of California, San Francisco, CA 94143-0556

Elevated plasma glutamate can cause selective loss of neurons in the brains of infant mice. The arcuate nucleus-median eminence region exhibits the greatest sensitivity to glutamate while it undergoes developmental maturation during early postnatal life. To investigate glutamate-induced cellular responses, groups of nursing 7-d-old mice (n = 31–93) were given single subcutaneous injections of 0.1–0.5 mg monosodium glutamate (MSG)/g body wt or an equivalent volume (30–50 µL) of water vehicle (n = 93). Injection of 0.2 mg MSG/g body wt produced a 16-fold rise in plasma glutamate after 15 min (2.10 vs. 0.122 mmol/L control) and was the lowest harmful dose tested. It not only induced injury of small bilateral groups of medial basal hypothalamic neurons at 5 h postinjection, but also enhanced their expression of the N-methyl-D-aspartate (NMDA)R1 glutamate receptor subunit. Higher dosages of 0.3–0.5 mg MSG/g body wt yielded dose-related increases in NMDAR1 staining intensity and larger numbers of damaged neurons within the ventromedial arcuate nucleus. Administration of the live-cell nuclear stain bis-benzimide (0.95 µmol/L) indicated that MSG accessed the entire brain (n = 20) and methylene blue (1.0 g/L) permeated extracellular spaces by 15 min postinjection (n = 19), before cell death was evident (0.75 mmol/L propidium iodide) from co-injected MSG. Immunostaining, which mimicked that for glial fibrillary acidic protein, suggested that glutamate was retained in tanycytes. We conclude that elevated plasma glutamate induces glutamate receptor expression during selective injury of ventromedial arcuate neurons and propose that by sequestering glutamate, tanycytes may amplify local concentrations and promote neuronal damage in infant mice.

KEY WORDS: • monosodium glutamate • arcuate nucleus • median eminence • glutamate receptor • CD1 mouse

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