Synchrotron XRF Imaging Reveals Manganese Accumulation in the Golgi and Post‐Synapses of Neurons and Enhanced Uptake in Astrocytes

ABSTRACT Manganese is an essential trace metal, but excessive exposure causes neurotoxicity, including parkinsonian syndromes, cognitive deficits, and may contribute to neurodegenerative diseases. Worldwide, tens of millions are exposed to elevated manganese in drinking water, exceeding World Health Organization guidelines. Despite its importance for public health, the cellular and subcellular mechanisms of manganese neurotoxicity remain poorly understood, particularly its distribution among brain cells and intracellular targets. We examined manganese accumulation in primary rat hippocampal neurons and astrocytes using a correlative imaging approach combining cryo‐fluorescence light microscopy and synchrotron X‐ray fluorescence imaging to map and quantify manganese at subcellular resolution. Manganese preferentially accumulated in the Golgi apparatus of neurons and astrocytes. In neurons, it was also present at the postsynaptic density, suggesting a role in synaptic vulnerability. Quantitative analysis showed that astrocytes accumulated about three times more manganese than neurons. Neuronal manganese uptake was reduced when neurons were co‐cultured with astrocytes, indicating a potential protective or buffering function of astrocytes. These findings identify critical cellular and subcellular targets of manganese, highlighting the Golgi apparatus as a central site in manganese neurotoxicity. This work advances understanding of cell type–specific responses to manganese exposure and may guide the development of targeted neuroprotective strategies.