Podium Presentation in Room 2 on Thursday at 16:10 (Chair: Livia Eberlin / Anand Mehta)
Authors: Elva Fridjonsdottir (1), Heather Hulme (1,2), Theodosia Vallianatou (1), Reza Shariatgorji (1,2), Anna Nilsson (1,2), Erwan Bezard (3,4), Xiaoqun Zhang (5), Per Svenningsson (5), Per E. Andrén (1,2)*
INTRODUCTION: Neurotransmitters and neuropeptides are important signaling molecules in the brain and alterations in their expression levels have been linked to neurological disorders such as Parkinson’s disease (PD). Current neuroimaging techniques have very limited abilities to directly identify and quantify neurotransmitters from brain sections. MALDI-MS imaging (MSI) can be used for the direct analysis of neurotransmitters, but has found only limited applications in the study of neurotransmitters due to their poor ionization efficiencies.
OBJECTIVES: The aim of this study was to develop and validate a method to image multiple neurotransmitters and neuropeptides in brain tissue sections by MALDI-MSI at high lateral resolution.
METHODS: We used FTICR MALDI-MSI for the comprehensive mapping of neurotransmitter networks in specific brain regions. Our new reactive MALDI matrix (FMP-10) facilitated the covalent charge-tagging of molecules containing phenolic hydroxyl and/or primary or secondary amine groups, including dopaminergic and serotonergic neurotransmitters and their associated metabolites. We illustrate the capabilities of the developed method on PD brain samples from human post-mortem tissue and animal (rat, primate) experimental models. We also studied L-DOPA-induced dyskinesia (LID) in PD.
RESULTS: The reactive MALDI matrix (FMP-10) improved the detection limit toward low-abundance neurotransmitters and facilitated the simultaneous imaging of neurotransmitters in fine structures of the brain. We imaged the metabolism of L-DOPA and the catecholaminergic pathway in LID and non-dyskinetic chronically L-DOPA treated PD primate brains. L-DOPA and the L-DOPA metabolite 3-O-methyldopa were highly elevated in the whole brain of dyskinetic animals resulting in significant increases in dopamine and downstream metabolites in all brain regions, except putamen and caudate. Dopamine formation was correlated with serotonin in specific layers of hippocampus in dyskinesia but not in the putamen. Using a rat model of PD, we imaged changes in enkephalins, dynorphins, tachykinins and neurotensin associated with the dopaminergic denervation and L-DOPA treatment in multiple brain regions. L-DOPA administration significantly affected neuropeptides in the globus pallidus, while neuropeptides in the caudate-putamen were mostly affected by dopamine depletion. Using high lateral resolution imaging, we observed an increase of neurotensin in the dorsal sub-region of the globus pallidus after dopamine depletion.
CONCLUSIONS: This study highlights the capacity of MALDI-MSI to elucidate the dynamics of neurotransmitter and neuropeptide signaling during PD and its treatment. Our results demonstrate the inability of extrastriatal brain areas to regulate the formation of dopamine during L-DOPA treatment, introducing the potential of dopamine to modulate neuronal signaling widely across the brain, resulting in unwanted side effects.
|Grants||yes||The Swedish RC, Swedish Foundation for Strategic Res., SciLifeLab|
|Board Member||yes||The Swedish Pharmaceutical Society|
|Planning to mention or discuss specific products or technology of the company(ies) listed above:||