Neuronal excitatory-to-inhibitory balance is altered in cerebral organoid models of genetic neurological diseases

• Published in: Molecular brain Vol. 14; no. 1; p. 156
• Main Authors: Foliaki, Simote T, Schwarz, Benjamin, Groveman, Bradley R, Walters, Ryan O, Ferreira, Natalia C, Orrù, Christina D, Smith, Anna, Wood, Aleksandar, Schmit, Olivia M, Freitag, Phoebe, Yuan, Jue, Zou, Wenquan, Bosio, Catharine M, Carroll, James A, Haigh, Cathryn L
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 11-10-2021; BioMed Central; BMC
• Subjects: Action Potentials; Alzheimer's disease; Brain Waves; Cell Differentiation; Chloride transport; Creutzfeldt-Jakob disease; Creutzfeldt-Jakob Syndrome - genetics; Creutzfeldt-Jakob Syndrome - pathology; Creutzfeldt-Jakob Syndrome - physiopathology; Down syndrome; Down Syndrome - genetics; Down Syndrome - pathology; Down Syndrome - physiopathology; Down's syndrome; Electrophysiology; Fibroblasts; Fibroblasts - cytology; Firing pattern; GABA; Gene mutations; Genetic aspects; Glutamatergic transmission; Homeostasis; Humans; Induced Pluripotent Stem Cells - physiology; Ion channels (ligand-gated); Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - genetics; Localization; Movement disorders; Mutation; Nerve Net - physiology; Neural oscillation; Neurodegeneration; Neurodegenerative diseases; Neurological diseases; Neuronal network communication; Neurons - physiology; Neurophysiology; Neurosteroids - pharmacology; Neurotransmitter Agents - metabolism; Neurotransmitters; Organoids; Organoids - physiology; Oscillations; Parkinson Disease - genetics; Parkinson Disease - pathology; Parkinson Disease - physiopathology; Parkinson's disease; Pregnanolone; Prion Proteins - genetics; Receptor mechanisms; Receptors, Neurotransmitter - metabolism; Synapses - metabolism; Trisomy; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; γ-Aminobutyric acid; γ-Aminobutyric acid receptors; Neurodegenerative diseases; Neural oscillation; Neuronal network communication
• ISSN: 1756-6606; 1756-6606
• DOI: 10.1186/s13041-021-00864-w

The neuro-physiological properties of individuals with genetic pre-disposition to neurological disorders are largely unknown. Here we aimed to explore these properties using cerebral organoids (COs) derived from fibroblasts of individuals with confirmed genetic mutations including PRNP
, trisomy 21 (T21), and LRRK2
, which are associated with Creutzfeldt Jakob disease, Down Syndrome, and Parkinson's disease. We utilized no known disease/healthy COs (HC) as normal function controls. At 3-4 and 6-10 months post-differentiation, COs with mutations showed no evidence of disease-related pathology. Electrophysiology assessment showed that all COs exhibited mature neuronal firing at 6-10 months old. At this age, we observed significant changes in the electrophysiology of the COs with disease-associated mutations (dCOs) as compared with the HC, including reduced neuronal network communication, slowing neuronal oscillations, and increased coupling of delta and theta phases to the amplitudes of gamma oscillations. Such changes were linked with the detection of hypersynchronous events like spike-and-wave discharges. These dysfunctions were associated with altered production and release of neurotransmitters, compromised activity of excitatory ionotropic receptors including receptors of kainate, AMPA, and NMDA, and changed levels and function of excitatory glutamatergic synapses and inhibitory GABAergic synapses. Neuronal properties that modulate GABAergic inhibition including the activity of Na-K-Cl cotransport 1 (NKCC1) in Cl
homeostasis and the levels of synaptic and extra-synaptic localization of GABA receptors (GABARs) were altered in the T21 COs only. The neurosteroid allopregnanolone, a positive modulator of GABARs, was downregulated in all the dCOs. Treatment with this neurosteroid significantly improved the neuronal communication in the dCOs, possibly through improving the GABAergic inhibition. Overall, without the manifestation of any disease-related pathology, the genetic mutations PRNP
, T21, and LRRK2
significantly altered the neuronal network communication in dCOs by disrupting the excitatory-to-inhibitory balance.