Subchronic Manganese Exposure Impairs Neurogenesis in the Adult Rat Hippocampus

Abstract

Adult neurogenesis takes place in the brain subventricular zone (SVZ) in the lateral walls of lateral ventricles and subgranular zone (SGZ) in the hippocampal dentate gyrus (HDG), and functions to supply newborn neurons for normal brain functionality. Subchronic Mn exposure is known to disrupt adult neurogenesis in the SVZ. This study was designed to determine whether Mn exposure disturbed neurogenesis within the adult HDG. Adult rats (10 weeks old) received a single dose of bromodeoxyuridine (BrdU) at the end of 4-week Mn exposure to label the proliferating cells. Immunostaining and cell counting data showed that BrdU(+) cells in Mn-exposed HDG were about 37% lower than that in the control (p < .05). The majority of BrdU(+) cells were identified as Sox2(+) cells. Another set of adult rats received BrdU injections for 3 consecutive days followed by 2- or 4-week Mn exposure to trace the fate of BrdU-labeled cells in the HDG. The time course studies indicated that Mn exposure significantly reduced the survival rate (54% at 2 weeks and 33% at 4 weeks), as compared with that in the control (80% at 2 weeks and 51% at 4 weeks) (p < .01). A significant time-dependent migration of newborn cells from the SGZ toward the granule cell layer was also observed in both control and Mn-exposed HDG. Triple-stained neuroblasts and mature neurons further revealed that Mn exposure significantly inhibited the differentiation of immature neuroblasts into mature neurons in the HDG. Taken together, these observations suggest that subchronic Mn exposure results in a reduced cell proliferation, diminished survival of adult-born neurons, and inhibited overall neurogenesis in the adult HDG. Impaired adult neurogenesis is likely one of the mechanisms contribute to Mn-induced Parkinsonian disorder.

Intracerebral Transplantation of Neural Stem Cells Restores Manganese-Induced Cognitive Deficits in Mice

“…Consistently, studies from other laboratories have also found that NSCs are the prime targets of Mn toxicity in both the DG and the SVZ [20]. These NSCs are stem celllike precursors that exist, predominantly, in these two brain regions to produce somatic cells such as neurons and glial cells in response to a variety of environmental conditions [20]. Furthermore, converging evidence has shown that NSCs in the brain undergoing differentiation and maturation play important roles in learning and memory functions [19,21], suggesting the potential of NSC transplantation as a promising tool to compensate for neuronal loss and structural damage in the adult hippocampus [20].…”

“…We and others have previously detected a decrease in the proliferation of multipotent neural stem cells (NSCs) within the hippocampal SGZ that was suggestive of disrupted neurogenesis that closely coincided with deficits in spatial recognition. Consistently, studies from other laboratories have also found that NSCs are the prime targets of Mn toxicity in both the DG and the SVZ [ 20 ]. These NSCs are stem cell-like precursors that exist, predominantly, in these two brain regions to produce somatic cells such as neurons and glial cells in response to a variety of environmental conditions [ 20 ].…”

“…Based on the strong link between adult hippocampal neurogenesis and learning and memory functions [ 20 ], a Mn exposure-induced reduction of hippocampal neurogenesis might cause deficits in spatial learning and memory tasks to a certain extent. Thus, we evaluated behavioral changes after enhancing neurogenesis by transplantation of cultured NSCs in the Mn-exposure model.…”

“…MnCl 2 • 4H 2 O dissolved in sterile saline was administrated to mice by intraperitoneal injection at a volume of 1 mL/kg body weight at a dose of 5mg/mL (referred to as low-dose exposure), 20 mg/mL (referred to as middle-dose exposure), and 50 mg/mL (referred to as high-dose exposure), once daily for two consecutive weeks. We and others have previously demonstrated that daily intraperitoneal administration of MnCl 2 at doses exceeding 5mg/kg body weight could produce a significantly elevated Mn concentration in the hippocampus in a dose-dependent manner after 14 consecutive days [20,30]. A daily equivalent volume of sterile saline was given to the sham control animals.…”

“…These NSCs are stem cell-like precursors that exist, predominantly, in these two brain regions to produce somatic cells such as neurons and glial cells in response to a variety of environmental conditions [ 20 ]. Furthermore, converging evidence has shown that NSCs in the brain undergoing differentiation and maturation play important roles in learning and memory functions [ 19 , 21 ], suggesting the potential of NSC transplantation as a promising tool to compensate for neuronal loss and structural damage in the adult hippocampus [ 20 ]. This would provide an indispensable source of new cells to support neuroplasticity and granule cell turnover that could lead to recovery from cognitive impairments [ 22 , 23 ].…”