Preweaning Mn exposure leads to prolonged astrocyte activation and lasting effects on the dopaminergic system in adult male rats

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.