Manganese Exposure Disrupts Glutamatergic Function and Alters Electroencephalogram Phenotypes: Relevance to Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) onset and progression can be influenced by modifiable risk factors such as the exposure to neurotoxic metals including manganese (Mn). Mn is an essential metal that serves as a cofactor for metalloenzymes important in modulating glutamatergic function and has been shown to directly impact glutamate clearance when present in excess. Glutamate dyshomeostasis is also observed in AD, with decreased expression in astrocytic glutamate reuptake transporters (GLT-1 and GLAST) being reported in brain tissue and in AD model systems. I hypothesized that Mn exposure in the context of a mouse model of AD would result in disruption of glutamatergic function including impaired glutamate clearance and excitatory/inhibitory imbalance resulting in epileptiform activity. Using the APPswe/PSEN1dE9 mouse model of AD and non-transgenic littermate controls, I observed changes in astrocytic glutamate clearance both in vitro in primary astrocytes and in ex vivo hippocampal slices. Additionally, I determined if Mn exposure increased seizure susceptibility and subclinical epileptiform activity using electroencephalogram recordings and an additional pharmacological challenge of kainic acid, an excitatory agonist. I found that Mn exposure increased seizure susceptibility in APPswe/PSEN1dE9 mice and controls, increased seizure severity in APPswe/PSEN1dE9 mice, and increased subclinical epileptiform activity in control mice. Additionally, I observed increased time awake and less time sleeping in control mice following Mn exposure. Mn exposure also resulted in shifts in different brain wave powerbands (e.g. Alpha, 8-12 Hz) with control mice showing more sensitivity to these changes compared to Mn treated APPswe/PSEN1dE9 mice. However, these changes were not explained by changes in GLT-1 and GLAST protein or RNA expression alone. These findings suggest that Mn exposure does impact glutamatergic homeostasis, and that Mn exposure and AD related pathology may be acting on similar mechanisms based on the changes observed herein between control and AD model mice.