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Neuroscience. 2019 Aug 7. pii: S0306-4522(19)30532-9. doi: 10.1016/j.neuroscience.2019.07.041. [Epub ahead of print]

Hyperexcitability in Cultured Cortical Neuron Networks from the G93A-SOD1 Amyotrophic Lateral Sclerosis Model Mouse and its Molecular Correlates.

Author information

1
Neurology IV -Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italy. Electronic address: stefania.marcuzzo@istituto-besta.it.
2
Neurophysiopathology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italy.
3
Neurology IV -Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italy.
4
Neurology IV -Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italy; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of Development and Stem Cells, CNRS UMR7104, INSERM U964, Université de Strasbourg, 67404 Illkirch CU, Strasbourg, France.
5
Laboratory of Clinical Pathology and Medical Genetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italy.
6
Neuroengineering and Medical Robotics Laboratory, Politecnico di Milano, Milan 20133, Italy; Currently working at Empatica srl, Milan 20144, Italy.
7
World Research Hub Initiative (WRHI), Institute of Innovative Research, Tokyo Institute of Technology, Yokohama 226-8503, Japan.
8
Department of Electronics, Information & Bioengineering, Politecnico di Milano, Milan 20133, Italy.
9
Neurophysiopathology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italy; Université Côte d'Azur, CNRS UMR7275, LabEx ICST, Institute of Molecular and Cellular Pharmacology, 06560 Valbonne-Sophia Antipolis, France.
10
World Research Hub Initiative (WRHI), Institute of Innovative Research, Tokyo Institute of Technology, Yokohama 226-8503, Japan; Complex Systems Theory Department, Institute of Nuclear Physics, Polish Academy of Sciences (IFJ-PAN), 31-342 Kraków, Poland; Center for Mind/Brain Sciences (CIMeC), University of Trento, 38123 Trento, Italy.

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the corticospinal tract and leading to motor neuron death. According to a recent study, magnetic resonance imaging-visible changes suggestive of neurodegeneration seem absent in the motor cortex of G93A-SOD1 ALS mice. However, it has not yet been ascertained whether the cortical neural activity is intact, or alterations are present, perhaps even from an early stage. Here, cortical neurons from this model were isolated at post-natal day 1 and cultured on multielectrode arrays. Their activity was studied with a comprehensive pool of neurophysiological analyses probing excitability, criticality and network architecture, alongside immunocytochemistry and molecular investigations. Significant hyperexcitability was visible through increased network firing rate and bursting, whereas topological changes in the synchronization patterns were apparently absent. The number of dendritic spines was increased, accompanied by elevated transcriptional levels of the DLG4 gene, NMDA receptor 1 and the early pro-apoptotic APAF1 gene. The extracellular Na+, Ca2+, K+ and Cl- concentrations were elevated, pointing to perturbations in the culture micro-environment. Our findings highlight remarkable early changes in ALS cortical neuron activity and physiology. These changes suggest that the causative factors of hyperexcitability and associated toxicity could become established much earlier than the appearance of disease symptoms, with implications for the discovery of new hypothetical therapeutic targets.

KEYWORDS:

APAF1 apoptosis-related gene; G93A-SOD1 mice; amyotrophic lateral sclerosis; cortical neurons; hyperexcitability; multi-electrode array (MEA)

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