C9orf72 hexanucleotide repeat expansion leads to altered neuronal and dendritic spine morphology and synaptic dysfunction

Nadine Huber; Dorit Hoffmann; Raisa Giniatullina; Hannah Rostalski; Stina Leskelä; Mari Takalo; Teemu Natunen; Eino Solje; Anne M. Remes; Rashid Giniatullin; Mikko Hiltunen; Annakaisa Haapasalo

Neurobiology of Disease (Jan 2022)

C9orf72 hexanucleotide repeat expansion leads to altered neuronal and dendritic spine morphology and synaptic dysfunction

Nadine Huber,
Dorit Hoffmann,
Raisa Giniatullina,
Hannah Rostalski,
Stina Leskelä,
Mari Takalo,
Teemu Natunen,
Eino Solje,
Anne M. Remes,
Rashid Giniatullin,
Mikko Hiltunen,
Annakaisa Haapasalo

Affiliations

Nadine Huber: Molecular Neurodegeneration group, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, 70211 Kuopio, Finland
Dorit Hoffmann: Molecular Neurodegeneration group, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, 70211 Kuopio, Finland
Raisa Giniatullina: Molecular Pain Research group, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, 70211 Kuopio, Finland
Hannah Rostalski: Molecular Neurodegeneration group, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, 70211 Kuopio, Finland
Stina Leskelä: Molecular Neurodegeneration group, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, 70211 Kuopio, Finland
Mari Takalo: Institute of Biomedicine, University of Eastern Finland, Yliopistonranta 1E, 70211 Kuopio, Finland
Teemu Natunen: Institute of Biomedicine, University of Eastern Finland, Yliopistonranta 1E, 70211 Kuopio, Finland
Eino Solje: Institute of Clinical Medicine - Neurology, University of Eastern Finland, Yliopistonranta 1 C, 70211 Kuopio, Finland; Neuro Center, Neurology, Kuopio University Hospital, P. O. Box 100, FI-70029 KYS, Finland
Anne M. Remes: Medical Research Center, Oulu University Hospital, P. O. Box 8000, FI-90014 University of Oulu, Finland; Unit of Clinical Neuroscience, Neurology, University of Oulu, P. O. Box 8000, FI-90014 University of Oulu, Finland
Rashid Giniatullin: Molecular Pain Research group, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, 70211 Kuopio, Finland
Mikko Hiltunen: Institute of Biomedicine, University of Eastern Finland, Yliopistonranta 1E, 70211 Kuopio, Finland
Annakaisa Haapasalo: Molecular Neurodegeneration group, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, 70211 Kuopio, Finland; Corresponding author at: Research Director of Molecular Neurodegeneration, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P. O. Box 1627, Neulaniementie 2, 70211 Kuopio, Finland.

Journal volume & issue: Vol. 162
p. 105584

Abstract

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Frontotemporal lobar degeneration (FTLD) comprises a heterogenous group of progressive neurodegenerative syndromes. To date, no validated biomarkers or effective disease-modifying therapies exist for the different clinical or genetic subtypes of FTLD. The most common genetic cause underlying FTLD and amyotrophic lateral sclerosis (ALS) is a hexanucleotide repeat expansion in the C9orf72 gene (C9-HRE). FTLD is accompanied by changes in several neurotransmitter systems, including the glutamatergic, GABAergic, dopaminergic, and serotonergic systems and many clinical symptoms can be explained by disturbances in these systems. Here, we aimed to elucidate the effects of the C9-HRE on synaptic function, molecular composition of synapses, and dendritic spine morphology. We overexpressed the pathological C9-HRE in cultured E18 mouse primary hippocampal neurons and characterized the pathological, morphological, and functional changes by biochemical methods, confocal microscopy, and live cell calcium imaging. The C9-HRE-expressing neurons were confirmed to display the pathological RNA foci and DPR proteins. C9-HRE expression led to significant changes in dendritic spine morphologies, as indicated by decreased number of mushroom-type spines and increased number of stubby and thin spines, as well as diminished neuronal branching. These morphological changes were accompanied by concomitantly enhanced susceptibility of the neurons to glutamate-induced excitotoxicity as well as augmented and prolonged responses to excitatory stimuli by glutamate and depolarizing potassium chloride as compared to control neurons. Mechanistically, the hyperexcitation phenotype in the C9-HRE-expressing neurons was found to be underlain by increased activity of extrasynaptic GluN2B-containing N-methyl-d-aspartate (NMDA) receptors. Our results are in accordance with the idea suggesting that C9-HRE is associated with enhanced excitotoxicity and synaptic dysfunction. Thus, therapeutic interventions targeted to alleviate synaptic disturbances might offer efficient avenues for the treatment of patients with C9-HRE-associated FTLD.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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