Preweaning Mn Exposure Leads to Prolonged Astrocyte Activation and Lasting Effects on the Dopaminergic System in Adult Male Rats

Overview

Journal Synapse

Specialty Neurology

Date 2010 Oct 22

PMID 20963817

Citations 38

Authors

Cynthia H Kern

Donald R Smith

Affiliations

Soon will be listed here.

Abstract

Little is known about the effects of manganese (Mn) exposure over neurodevelopment and whether these early insults result in effects lasting into adulthood. To determine if early Mn exposure produces lasting neurobehavioral and neurochemical effects, we treated neonate rats with oral Mn (0, 25, or 50 mg Mn/kg/d over PND 1-21) and evaluated (1) behavioral performance in the open arena in the absence (PND 97) and presence (PND 98) of a d-amphetamine challenge, (2) brain dopamine D1 and D2-like receptors and dopamine transporter densities in the prefrontal cortex, striatum, and nucleus accumbens (PND 107), and (3) astrocyte marker glial fibrillary acidic protein (GFAP) levels in these same brain regions (PND 24 and 107). We found that preweaning Mn exposure did not alter locomotor activity or behavior disinhibition in adult rats, though Mn-exposed animals did exhibit an enhanced locomotor response to d-amphetamine challenge. Preweaning Mn exposure led to increased D1 and D2 receptor levels in the nucleus accumbens and prefrontal cortex, respectively, compared with controls. We also found increased GFAP expression in the prefrontal cortex in Mn-exposed PND 24 weanlings, and increased GFAP levels in prefrontal cortex, medial striatum and nucleus accumbens of adult (PND 107) rats exposed to preweaning Mn, indicating an effect of Mn exposure on astrogliosis that persisted and/or progressed to other brain regions in adult animals. These data show that preweaning Mn exposure leads to lasting molecular and functional impacts in multiple brain regions of adult animals, long after brain Mn levels returned to normal.

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References

Surmeier D, Ding J, Day M, Wang Z, Shen W . D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons. Trends Neurosci. 2007; 30(5):228-35. DOI: 10.1016/j.tins.2007.03.008. View

Arnsten A, Goldman-Rakic P . Noise stress impairs prefrontal cortical cognitive function in monkeys: evidence for a hyperdopaminergic mechanism. Arch Gen Psychiatry. 1998; 55(4):362-8. DOI: 10.1001/archpsyc.55.4.362. View

Keen C, Lonnerdal B, Clegg M, Hurley L . Developmental changes in composition of rat milk: trace elements, minerals, protein, carbohydrate and fat. J Nutr. 1981; 111(2):226-36. DOI: 10.1093/jn/111.2.226. View

Verity M . Manganese neurotoxicity: a mechanistic hypothesis. Neurotoxicology. 1999; 20(2-3):489-97. View

Hazell A . Astrocytes and manganese neurotoxicity. Neurochem Int. 2002; 41(4):271-7. DOI: 10.1016/s0197-0186(02)00013-x. View

Cory-Slechta D, Pokora M, Widzowski D . Postnatal lead exposure induces supersensitivity to the stimulus properties of a D2-D3 agonist. Brain Res. 1992; 598(1-2):162-72. DOI: 10.1016/0006-8993(92)90180-h. View

Kontur P, Fechter L . Brain manganese, catecholamine turnover, and the development of startle in rats prenatally exposed to manganese. Teratology. 1985; 32(1):1-11. DOI: 10.1002/tera.1420320102. View

Russell V . Dopamine hypofunction possibly results from a defect in glutamate-stimulated release of dopamine in the nucleus accumbens shell of a rat model for attention deficit hyperactivity disorder--the spontaneously hypertensive rat. Neurosci Biobehav Rev. 2003; 27(7):671-82. DOI: 10.1016/j.neubiorev.2003.08.010. View

Mergler D, Huel G, Bowler R, Iregren A, Belanger S, Baldwin M . Nervous system dysfunction among workers with long-term exposure to manganese. Environ Res. 1994; 64(2):151-80. DOI: 10.1006/enrs.1994.1013. View

10.

Arnsten A . Fundamentals of attention-deficit/hyperactivity disorder: circuits and pathways. J Clin Psychiatry. 2006; 67 Suppl 8:7-12. View

11.

Carr D, ODonnell P, Card J, Sesack S . Dopamine terminals in the rat prefrontal cortex synapse on pyramidal cells that project to the nucleus accumbens. J Neurosci. 1999; 19(24):11049-60. PMC: 6784921. View

12.

Yamada M, Ohno S, Okayasu I, Okeda R, Hatakeyama S, Watanabe H . Chronic manganese poisoning: a neuropathological study with determination of manganese distribution in the brain. Acta Neuropathol. 1986; 70(3-4):273-8. DOI: 10.1007/BF00686083. View

13.

Heales S, Bolanos J, Stewart V, Brookes P, Land J, Clark J . Nitric oxide, mitochondria and neurological disease. Biochim Biophys Acta. 1999; 1410(2):215-28. DOI: 10.1016/s0005-2728(98)00168-6. View

14.

Collipp P, Chen S, Maitinsky S . Manganese in infant formulas and learning disability. Ann Nutr Metab. 1983; 27(6):488-94. DOI: 10.1159/000176724. View

15.

Ericson J, Crinella F, Clarke-Stewart K, Allhusen V, Chan T, Robertson R . Prenatal manganese levels linked to childhood behavioral disinhibition. Neurotoxicol Teratol. 2006; 29(2):181-7. DOI: 10.1016/j.ntt.2006.09.020. View

16.

Barhoumi R, Faske J, Liu X, Tjalkens R . Manganese potentiates lipopolysaccharide-induced expression of NOS2 in C6 glioma cells through mitochondrial-dependent activation of nuclear factor kappaB. Brain Res Mol Brain Res. 2004; 122(2):167-79. DOI: 10.1016/j.molbrainres.2003.12.009. View

17.

He P, Liu D, Zhang G . [Effects of high-level-manganese sewage irrigation on children's neurobehavior]. Zhonghua Yu Fang Yi Xue Za Zhi. 1994; 28(4):216-8. View

18.

CHANDRA S, Shukla G, Saxena D . Manganese-induced behavioral dysfunction and its neurochemical mechanism in growing mice. J Neurochem. 1979; 33(6):1217-21. DOI: 10.1111/j.1471-4159.1979.tb05267.x. View

19.

Wright R, Amarasiriwardena C, Woolf A, Jim R, Bellinger D . Neuropsychological correlates of hair arsenic, manganese, and cadmium levels in school-age children residing near a hazardous waste site. Neurotoxicology. 2005; 27(2):210-6. DOI: 10.1016/j.neuro.2005.10.001. View

20.

Decker M, Jones K, Solomon I, Keating G, Rye D . Reduced extracellular dopamine and increased responsiveness to novelty: neurochemical and behavioral sequelae of intermittent hypoxia. Sleep. 2005; 28(2):169-76. DOI: 10.1093/sleep/28.2.169. View