Neurochemical Profile of BRAFV600E/AktT308D/S473D Mouse Gangliogliomas Reveals Impaired GABAergic System Inhibition.

Autor:	Kyriazi M; Institute of Neuropathology, Section for Translational Epilepsy Research, Medical Faculty, University of Bonn, Bonn, Germany., Müller P; Institute of Neuropathology, Section for Translational Epilepsy Research, Medical Faculty, University of Bonn, Bonn, Germany., Pitsch J; Department of Epileptology, Medical Faculty, University of Bonn, Bonn, Germany., van Loo KMJ; Department of Epileptology, Neurology, RWTH Aachen University, Aachen, Germany., Quatraccioni A; Institute of Neuropathology, Section for Translational Epilepsy Research, Medical Faculty, University of Bonn, Bonn, Germany., Opitz T; Institute of Experimental Epileptology and Cognition Research, Medical Faculty, University of Bonn, Bonn, Germany., Schoch S; Institute of Neuropathology, Section for Translational Epilepsy Research, Medical Faculty, University of Bonn, Bonn, Germany.; Department of Epileptology, Medical Faculty, University of Bonn, Bonn, Germany., Becker AJ; Institute of Neuropathology, Section for Translational Epilepsy Research, Medical Faculty, University of Bonn, Bonn, Germany., Cases-Cunillera S; Institute of Neuropathology, Section for Translational Epilepsy Research, Medical Faculty, University of Bonn, Bonn, Germany.
Jazyk:	angličtina
Zdroj:	Developmental neuroscience [Dev Neurosci] 2023; Vol. 45 (2), pp. 53-65. Date of Electronic Publication: 2022 Dec 20.
DOI:	10.1159/000528587
Abstrakt:	Gangliogliomas (GGs), composed of dysmorphic neurons and neoplastic astroglia, represent the most frequent tumor entity associated with chronic recurrent epileptic seizures. So far, a systematic analysis of potential differences in neurochemical profiles of dysmorphic tumoral neurons as well as neurons of the peritumoral microenvironment (PTME) was hampered by the inability to unequivocally differentiate between the distinct neuronal components in human GG biopsies. Here, we have applied a novel GG mouse model that allows to clearly resolve the neurochemical profiles of GG-intrinsic versus PTME neurons. For this purpose, glioneuronal tumors in mice were induced by intraventricular in utero electroporation (IUE) of piggyBac-based plasmids for BRAFV600E and activated Akt (AktT308D/S473D, further referred to as AktDD) and analyzed neurochemically by immunocytochemistry against specific marker proteins. IUE of BRAFV600E/AktDD in mice resulted in tumors with the morphological features of human GGs. Our immunocytochemical analysis revealed a strong reduction of GABAARα1 immunoreactivity in the tumor compared to the PTME. In contrast, the extent of NMDAR1 immunoreactivity in the tumor appeared comparable to the PTME. Interestingly, tumor cells maintained the potential to express both receptors. Fittingly, the abundance of the presynaptic vesicular neurotransmitter transporters VGLUT1 and VGAT was also decreased in the tumor. Additionally, the fraction of parvalbumin and somatostatin nonneoplastic interneurons was reduced. In conclusion, changes in the levels of key proteins in neurotransmitter signaling suggest a loss of synapses and may thereby lead to neuronal network alterations in mouse GGs. (The Author(s). Published by S. Karger AG, Basel.)
Databáze:	MEDLINE
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